Gina Mauro

This content originally appeared on our sister site, 

The FDA has approved olaparib (Lynparza) as an earlier line of adjuvant therapy in patients with 

, marking the first approved therapy to treat early, 

mutated population has been established as an especially at-risk population for aggresive and recurrent breast cancers. Olaparibn's earlier line approval may mark a shift in prioritizing the role of genetic testing in the diagnosis and treatment of patients with breast cancer.

“Today’s approval of olaparib is great news for patients with a specific inherited form of breast cancer," Professor Andrew Tutt, global chair of the OlympiA trial and professor of oncology at The Institute of Cancer Research, London and King’s College London, said in a press release.

The approval is based on data from the phase 3 OlympiA trial (NCT02032823), in which participants who have previously received chemotherapy treated with olaparib either before or after surgery demonstrated a 42% improvement in invasive disease-free survival (iDFS) compared with placebo (HR, 0.58; 95% CI, 0.46-0.74; 

Cilta-Cel Approved for Relapsed/Refractory Multiple Myeloma

Adjuvant olaparib also decreased risk of disease progression or death by 32% compared with placebo (HR, 0.68; 95% CI, 0.50-0.91; 

 = .0091). Data on OS were presented at the European Society for Medical Oncology (ESMO) virtual plenary on March 16, 2022. There were 75 deaths (8%) in the olaparib arm and 109 deaths (12%) in the placebo arm (HR, 0.68 [95% CI, 0.50-0.91]; 

"Most breast cancers are identified in the early stages and many patients will do very well, but for those with higher risk disease at diagnosis, the risk of cancer returning can be unacceptably high and new treatment options are needed. OlympiA has shown that identifying a 

 mutation in women with high risk disease opens the additional option of eligibility for olaparib treatment, which reduces the risk of recurrence and improves survival for these breast cancer patients," Tutt added.

The multicenter, randomized, placebo-controlled OlympiA trial enrolled 1836 patients with HER2-negative breast cancer harboring a germline 

 mutation. Patients were randomized 1:1 to receive 300 mg of oral olaparib twice daily for 1 year (n = 921) or placebo (n = 915). Additionally, patients had to have been treated for stage II or III breast cancer, and have completed surgery and chemotherapy, with or without radiotherapy.

The primary end point for the study was iDFS; secondary end points included distant disease-free survival (DDFS), overall survival (OS), health-related quality of life, and safety.

Additional findings indicated that patients who received olaparib experienced a 43% reduction in DDFS, including metastatic disease, new cancer, and death due to any cause (stratified HR, 0.57; 99.5% CI, 0.39-0.83; 

 < .0001). The difference in the 3-year DDFS rate between olaparib and placebo was 7.1% (87.5% vs 80.4%, respectively; 95% CI, 3.0%-11.1%).

The therapy was generally well-tolerated, with adverse events (AEs) reported in the olaparib arm consistent with previous data on the therapy. Additionally, olaparib did not increase serious AEs, including hospital admissions or occurrences of other cancers, such as leukemia.

However, grade 3 or higher AEs were reported more often in patients who received olaparib, and included anemia (9%), neutropenia (5%), leukopenia (3%), and fatigue (2%).

The most common AEs of any-grade reported in patients who received olaparib included nausea (57%), fatigue (40%), anemia (23%), vomiting (23%), and headache (20%). The most common AEs of any-grade reported in the placebo arm were fatigue (27%), nausea (23%), headache (17%), diarrhea (14%), and arthralgia (12%).

“This important approval gives early-stage breast cancer patients in the US with a germline BRCA mutation a new targeted therapy option in the adjuvant setting starting today. Lynparza reduces the risk of disease recurrence in these high-risk patients and now new data confirm it also significantly extends patients’ lives versus placebo. These data underline the importance of germline BRCA testing as soon as possible after diagnosis to identify patients that may be eligible for Lynparza," Dave Fredrickson, executive vice president, Oncology Business Unit, AstraZeneca, added to the statement.

Lynparza approved in the US as adjuvant treatment for patients with germline BRCA-mutated HER2-negative high-risk early breast cancer. AstraZeneca. News release. March 11, 2022. Accessed March 11, 2022. https://bit.ly/3tQePcn

Tutt ANJ, Garber JE, Kaufman B, et al. Adjuvant olaparib for patients with 

. 2021;384(25):2394-2405. doi:10.1056/NEJMoa2105215

Tutt A, Garber JE, Kaufman B, et al. OlympiA: a phase III, multicenter, randomized, placebo-controlled trial of adjuvant olaparib after (neo)adjuvant chemotherapy in patients with germline 

 mutations and high-risk HER2-negative early breast cancer. 

. 2021;39(suppl 15):LBA1. doi:10.1200/JCO.2021.39.15_suppl.LBA1

FDA approves olaparib for adjuvant treatment of high-risk early breast cancer. News release. ESMO. March 18, 2022. https://www.esmo.org/oncology-news/fda-approves-olaparib-for-adjuvant-treatment-of-high-risk-early-breast-cancer

Articles

Olaparib is now the first early-line therapy targeting BRCA-mutations in breast cancer.

Adjuvant Olaparib Approved for BRCA+, High-Risk Early Breast Cancer

This article originally appeared on our sister site, 

Ciltacabtagene autoleucel (cilta-cel; Carvykti) has been granted FDA approval for the treatment of adult patients with relapsed/refractory multiple myeloma following 4 or more prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

The CAR T-cell therapy co-developed by Janssen and Legend Biotech demonstrated efficacy in the phase 1b/2 CARTITUDE-1 trial (NCT03548207), in which cilta-cel elicited an objective response rate (ORR) of 98% (95% CI, 92.7%-99.7%) in this patient population,

 as well as a complete response rate (sCR) of 78% (95% CI, 68.8%-86.1%). The median duration of response (DOR) was 21.8 months at a median 18 months of follow-up.

“The responses in the CARTITUDE-1 study showed durability over time and resulted in the majority of heavily pretreated patients achieving deep responses after 18-month follow-up,” principal investigator Sundar Jagannath, MD, director of the Center of Excellence for Multiple Myeloma and professor of medicine, hematology and medical oncology, at The Tisch Cancer Institute at the Icahn School of Medicine at Mount Sinai, stated in a press release. “The approval of cilta-cel provides physicians an immunotherapy treatment option that offers patients an opportunity to be free from anti-myeloma therapies for a period of time.”

In November 2021, the FDA had extended the Prescription Drug User Fee Act target date for the biologics license application (BLA) seeking the approval of cilta-cel for use in adult patients with relapsed and/or refractory multiple myeloma.

On October 28, 2021, Janssen was alerted of the extension to allow for adequate time to review recently submitted data associated with an updated analytical method following an information request issued by the regulatory agency. Shortly after, on November 1, 2021, Janssen and Legend Biotech Corporation met with the FDA, and no additional clinical data were requested.

Due to the FDA's requests, the new decision date for the application had been moved to February 28, 2022.

The single-arm, open-label, phase 1b/2 trial enrolled patients with multiple myeloma who were at least 18 years of age, had measurable disease at screening, and an ECOG performance status of 0 or 1.

 Patients needed to have previously received 3 or more prior lines of therapy or become double refractory to a proteasome inhibitor and an immunomodulatory drug, and have received a proteasome inhibitor, immunomodulatory drug, and an anti-CD38 antibody, with documented progressive disease.

If patients previously received treatment with a CAR T-cell– or BCMA-targeted therapy, they were excluded.

Patients’ blood was apheresed in accordance with institutional standards. Between apheresis and CAR T-cell infusion, patients were permitted to receive bridging therapy if clinically indicated. After the successful manufacturing of cilta-cel, patients underwent lymphodepletion with cyclophosphamide at 300 mg/m

, both administered daily for 3 days. Five to 7 days following the initiation of lymphodepletion, patients were administered a single infusion at a target dose of 0.75 x 10

 CAR-positive viable T cells/kg (range, 0.5 x 10

The primary end point of the phase 1b portion of trial was to examine the incidence and severity of adverse effects (AEs). The primary end point of the phase 2 portion was ORR. Secondary end points in both phases included sCR, complete response (CR), very good partial response (VGPR), DOR, rate of minimal residual disease negativity, PFS, and OS. Investigators also evaluated pharmacokinetic and pharmacodynamic markers.

A total of 113 patients were enrolled to the trial and all underwent apheresis. Fourteen percent of patients did not receive the CAR T-cell therapy because of progressive disease (n = 2), study withdrawal (n = 2), or death (n = 8). A total of 101 patients underwent lymphodepletion; of these patients, 4 discontinued.

A total of 97 patients received cilta-cel; 29 of these patients received the product in the phase 1b portion and 68 did so in the phase 2 portion. Twenty-four patients in the phase 1b portion were still receiving treatment, as were 59 patients in the phase 2 portion.

The median age of patients was 61.0 years (IQR, 56.0-68.0), and 59% of patients were male. Moreover, most patients were White and non-Hispanic or non-Latino. Additionally, 24% of patients had a high-risk cytogenetic profile based on the presence of del(17p), t(14;16), or t(4;14), and 13% had extramedullary plasmacytomas at screening.

The median time from diagnosis was 5.9 years (IQR, 4.4-8.4), and patients received a median of 6 prior therapies (IQR, 4.0-8.0). Eighty-four percent of patients had been exposed to 5 drugs. Moreover, 84% were refractory to pomalidomide (Pomalyst), 65% to carfilzomib (Kyprolis), and 99% to anti-CD38 antibody treatment. Eighty-eight percent of patients were triple-class refractory, 42% were penta-drug refractory, and 99% were refractory to their last lane of therapy received.

Additional data showed that among those who achieved a CR or better, the 12-month PFS rate was 85% (95% CI, 72.0%-91.8%). In those who achieved a VGPR, this rate was 62% (95% CI, 42.1%-76.9%). Moreover, response rates were noted to be similar across the prespecified subsets analyzed.

Regarding safety, all patients experienced toxicities, including grade 3 or 4 effects. The most common AEs reported were hematologic in nature; grade 3 or 4 hematologic toxicities included neutropenia (95%), anemia (68%), leukopenia (61%), thrombocytopenia (60%), and lymphopenia (50%).

Those who had grade 3 or 4 cytopenic events following day 1 of CAR T-cell infusion recovered to grade 2 or less by day 30 for lymphopenia (88%), neutropenia (70%), and thrombocytopenia (59%).

Longer follow-up from the CARTITUDE-1 trial was presented during the 2021 ASH Annual Meeting and Exposition.

 Data from a 2-year follow-up analysis of the study demonstrated that all patient subgroups had achieved a consistently high ORR comparable with that of the overall patient population, with a range from 95.1% to 100%. Additionally, in all subgroups, 80% to 100% of minimal residual disease (MRD)-evaluable patients achieved MRD negativity at a 10-5 threshold.

In patients who were aged 65 years and older (n = 35), 8 of whom were 75 years and older, the ORR was 97.1% (95% CI, 85.1%-99.9%) and the MRD negativity rate was 91.3% (95% CI, 72%-98.9%).

Cilta-cel is available through the restricted CARVYKTI™ Risk Evaluation and Mitigation Strategy Program. There is also a boxed warning for this treatment regarding cytokine release syndrome, immune effector cell-associated neurotoxicity syndrome, Parkinsonism and Guillain-Barré syndrome, hemophagocytic lymphohistiocytosis/macrophage activation syndrome, and prolonged and/or recurrent cytopenias.

“We are committed to harnessing our science, deep disease understanding and capabilities to bring forward cell therapies like Carvykti as we continue to focus on our ultimate goal of delivering a cure for multiple myeloma,” Peter Lebowitz, MD, PhD, global therapeutic area head, oncology, Janssen Research & Development, LLC, which develops cilta-cel with Legend Biotech, stated in a press release. “We extend our sincere gratitude to the patients, their families and the teams of researchers and study centers who have participated in the clinical study of Carvykti and enabled today’s approval.”

U.S. FDA approves CARVYKTI™ (ciltacabtagene autoleucel), Janssen’s first cell therapy, a BCMA-directed CAR-T immunotherapy for the treatment of patients with relapsed or refractory multiple myeloma. News release. Janssen. February 28, 2022. Accessed February 28, 2022. https://bit.ly/35yWwjv

Carvykti (ciltacabtagene autoleucel) suspension for intravenous infusion. Prescribing information. Janssen Biotech and Legend Biotech Corporation; 2022. Accessed February 28, 2022.

Legend Biotech announces extension of PDUFA date for cilta-cel. News release. Legend Biotech Corporation. November 1, 2021. Accessed November 2, 2021. https://bit.ly/3GNZcIm

Berdeja JG, Madduri D, Usmani SZ, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. 

. 2021;398(10297):314-324. doi:10.1016/S0140-6736(21)00933-8

Jakubowiak A, Usmani SZ, Berdeja JG, et al. Efficacy and safety of ciltacabtagene autoleucel in patients With relapsed/refractory multiple myeloma: CARTITUDE-1 subgroup analysis. 

. 2021;138(suppl_1):3938. doi:10.1182/blood-2021-146069

The CAR T-cell therapy from Janssen and Legend Biotech is the second to receive approval with an indication for treatment of multiple myeloma. 

CYNK-001, a non-genetically modified cryopreserved human placental hematopoietic stem cell-derived natural killer (NK) cell therapy in development by Celularity, has been granted Fast Track Designation by the US Food and Drug Administration (FDA) for the potential treatment of patients with acute myeloid leukemia (AML).

“The majority of patients with AML continue to have poor long-term outcomes, particularly those who suffer relapse or have measurable residual disease, necessitating development of novel therapies, including CYNK-001,”  Andrew Pecora, MD, president of Celularity, said in a press release.

CYNK-001 is a cryopreserved allogeneic off-the-shelf cell therapy enriched for CD56+/CD3- NK cells expanded from human placental CD34+ cells. Celularity noted that the safety and efficacy of CYNK-001 have not yet been established.

In June 2021, it was announced that a phase 1 study (NCT04310592) evaluating CYNK-001 had expanded to include patients with relapsed/refractory AML after a case of conversion to minimal residual disease (MRD) negativity at its highest dose level.

 The expansion is in addition to the ongoing trial’s population of patients with MRD-positive disease.

-negative AML who had received 5.4 billion CYNK-001 cells, did not experience a dose-limiting toxicity (DLT), and converted from MRD-positive disease to MRD-negative disease upon assessment. The patient also had good-risk cytogenetics.

Following primary induction therapy with 7+3 chemotherapy that failed, the patient received second induction treatment followed by high-dose cytarabine consolidation. The patient experienced a complete clinical response (CR); however, the MRD was persistent and did not clear after 4 months of azacitidine; MRD was confirmed on a marrow biopsy.

The patient then entered on the phase 1 trial and received lymphodepletion before receiving 1.8 billion CYNK-001 cells on days 0, 7, and 14 in the outpatient setting, totaling to 5.4 billion CYNK-001 cells. On day 28, the patient not only had confirmed conversion from MRD-positive to MRD-negative disease, but CYNK-001 cells were present in both the peripheral blood and bone marrow.

In the open-label, multi-dose, phase 1 trial, investigators are evaluating the maximum-tolerated dose (MTD) or maximum-planned dose of CYNK-001 in an estimated 22 patients with AML.

 The estimated completion date of the trial is January 3, 2022.

To be eligible for enrollment, patients must have primary or secondary AML who are in first of second morphological CR, morphological CR with incomplete hematologic recovery, or morphologic leukemia-free state as defined by the European LeukemiaNet recommendations for AML Response Criteria. Additional eligibility criteria include MRD positivity, between the ages of 18 and 80 years old, an ECOG performance status of 2 or lower, and the ability to be off immunosuppressive therapy for at least 3 days prior to CYNK-001 infusion.

Prior central nervous system involvement is permitted if it was treated, and cerebral spinal fluid is clear for at least 2 weeks prior to start of lymphodepletion.

Those who have any significant medical conditions that would prevent them from participating on the trial, laboratory abnormalities, bi-phenotypic acute leukemia, acute promyelocytic leukemia, inadequate organ function, autoimmune disease, and uncontrolled graft-vs-host disease (GVHD) or GVHD requiring corticosteroids, among other factors, were excluded from enrollment.

Patients are administered cyclophosphamide and fludarabine followed by CYNK-001 at 3 varying dose levels on days 0, 7, and 14. The primary end points of the trial are the number of patients who experience a DLT, MTD, and frequency and severity of adverse effects. Secondary outcome measures include the number of patients who convert from MRD positivity to negativity, time to and duration of MRD response, progression-free survival, time to progression, duration of morphologic complete remission, and overall survival.

Celularity has previously stated that it intends to continue dose escalation in the MRD indication to a total 9.0 billion CYNK-001 cells in addition to expanding the study to include those with relapsed/refractory AML.

“We believe that the unique properties of our cell source, including the ability to proliferate and maintain activity, could be the key to improving response rates and durability for patients," Robert Hariri, MD, PhD, founder, chairperson, and chief executive officer of Celularity, said in the press release. "We are pleased to receive this fast-track designation from the FDA for AML supporting continued development of our placental-derived NK cell platform." 

CYNK-001 previously was granted Orphan Drug Designation for malignant gliomas and Fast Track Designation for glioblastoma multiforme, Hariri added. 

Celularity Receives Fast Track Designation from U.S. FDA for its NK Cell Therapy CYNK-001 in Development for the Treatment of AML. Celularity. News release. December 27, 2021. Accessed December 27, 2021. https://bit.ly/3euVWEO

Celularity announces expansion of human placental hematopoietic stem cell derived natural killer cells (CYNK-001) phase 1 trial in patients with acute myeloid leukemia. News release. Celularity. June 29, 2021. Accessed June 29, 2021.

Natural killer cell (CYNK-001) infusions in adults with AML (CYNK001AML01). ClinicalTrials.gov. Updated March 2, 2021. Accessed June 29, 2021. 

https://clinicaltrials.gov/ct2/show/NCT04310592

CYNK-001, a non-genetically modified cryopreserved human placental hematopoietic stem cell-derived natural killer cell therapy, is in development for the potential treatment of patients with acute myeloid leukemia.

Celularity's CYNK-001 Cell Therapy for AML Granted FDA Fast Track Designation

Gavocabtagene autoleucel (gavo-cel; TC-210; TCR

 as a potential treatment of cholangiocarcinoma.

Gavo-cel is a novel, autologous cell therapy defined as T-cell receptor (TCR) fusion construct T cells (TRuC-T cells). It is currently being evaluated in a phase 1/2 trial (NCT03907852) in treatment-refractory mesothelin-expressing solid tumors. Findings from the study, which will comprise data from patients with malignant mesothelioma, ovarian cancer, and cholangiocarcinoma, will be presented at the 2021 ESMO Congress.

Mesothelin is described as a cell-surface glycoprotein highly expressed in several solid malignancies, including malignant pleural/peritoneal mesothelioma, ovarian cancer, cholangiocarcinoma, breast cancer, and pancreatic cancer. Moreover, mesothelin overexpression is linked with worse prognosis in select tumors; it has an active role in malignant transformation and tumor aggressiveness via promotion of cancer cell proliferation, invasion, and metastasis.

Non–small cell lung cancers (NSCLCs), ovarian cancers, mesotheliomas and cholangiocarcinomas that express mesothelin comprise 80,000 patients in the United States each year.

First Patient Dosed in Trial of GEN-011 for Treating Solid Tumors

Gavo-cel is described as autologous genetically engineered T cells that express a single-domain antibody with the ability to recognize human mesothelin that is fused to CD3-epsilon subunit; this is incorporated into the endogenous T-cell receptor complex.

Preclinical data showed that TRuC-T cells demonstrated encouraging activity compared with CAR T-cell therapy, while secreting lower levels of cytokine release.

In the ongoing, phase 1/2 trial, investigators sought to determine the recommended phase 2 dose (RP2D) of gavo-cel (phase 1 portion) as well as the overall response rate (ORR; phase 2) in approximately 70 patients with advanced mesothelin-expressing, unresectable, metastatic, or recurrent cancers.

 As part of a lymphodepletion regimen, fludarabine will be administered at 30 mg/m

 daily on days -7 through -4 and cyclophosphamide at 600 mg/m2 daily on days -6 through -4 followed by gavo-cel.

To be eligible for enrollment, patients aged 18 years or older must have a confirmed diagnosis of malignant pleural/peritoneal mesothelioma, serous ovarian adenocarcinoma, cholangiocarcinoma, or NSCLC; have mesothelin expression on more than 50% of tumor cells that are immunohistochemistry 2+ and/or 3+; must have received at least 1 systemic standard treatment for metastatic or unresectable disease; an ECOG performance status of 0 or 1; a left ventricular ejection fraction greater than 45%; fit for leukapheresis and has adequate venous access for cell collection; and must have adequate organ function.

In December 2020, TCR2 Therapeutics announced interim findings from the phase 1 portion of the trial.

 As of the data cutoff date of November 24, 2020, which had data from the first 8 patients, results showed that there were 3 partial responses (PRs) via RECIST v1.1 criteria. The first patient with ovarian cancer on study achieved a confirmed PR up until 6 months.

Additional data showed that the first patient who received gavo-cel at a higher dose, 1 x 108/m

, without lymphodepletion had stable disease for 2 months and did not experience significant toxicities. There were also reports of TRuC-T cell expansion and cytokine induction in all patients.

Regarding safety, 2 patients as of the data cutoff data reported treatment-related non-hematologic toxicities that were higher than grade 2; there was no evidence of neurotoxicity nor on-target/off-tumor toxicity.

TC-110, another TRuC-T cell product, is being studied in an ongoing phase 1/2 trial of adult patients with CD19-positive acute lymphoblastic leukemia and with aggressive or indolent non-Hodgkin lymphoma.

1. TCR² Therapeutics Receives FDA Orphan Drug Designation for Gavo-cel for the Treatment of Cholangiocarcinoma. News release. TCR2 Therapeutics. September 2, 2021. Accessed September 2, 2021. https://bit.ly/2V8GibVA
2. Phase 1/2 Single Arm Open-Label Clinical Trial of Gavocabtagene Autoleucel (Gavo-cel) in Patients With Advanced Mesothelin-Expressing Cancer. ClinicalTrials.gov. Updated June 29, 2021. Accessed September 2, 2021. https://clinicaltrials.gov/ct2/show/NCT03907852
3. TCR² Announces RECIST Response in Ovarian Cancer from Ongoing Phase 1/2 Trial of Tc-210 in Treatment Refractory Mesothelin-Expressing Solid Tumors. News release. TCR2 Therapeutics. December 13, 2020. Accessed September 2, 2021. https://bit.ly/2WHdV58

The investigational cell therapy consists of T-cell receptor (TCR) fusion construct T cells (TRuC-T cells).

Gavo-Cel Granted Orphan Drug Designation for Cholangiocarcinoma

Celularity, a clinical-stage biotechnology company, has announced that it is expanding its phase 1 study (NCT04310592) of CYNK-001, an off-the-shelf allogeneic unmodified natural killer (NK) cell therapy, to include patients with relapsed/refractory 

 (AML) in addition to its original population of patients with minimal residual disease (MRD) positivity. 

The expansion follows a case of conversion from MRD-positive disease to MRD negativity in a patient with 

-negative AML who had received 5.4 billion CYNK-001 cells, the highest dose level currently being assessed. The patient did not experience a dose-limiting toxicity (DLT) and had good-risk cytogenetics.

After primary induction treatment with 7+3 chemotherapy failed, the patient received second induction treatment followed by high-dose cytarabine consolidation. The patient experienced a complete clinical response (CR); however, the MRD was persistent and did not clear after 4 months of azacitidine; MRD was confirmed on a marrow biopsy.

The patient then entered the phase 1 trial and received lymphodepletion before receiving 1.8 billion CYNK-001 cells on days 0, 7, and 14 in the outpatient setting, totaling to 5.4 billion CYNK-001 cells. On day 28, the patient not only had confirmed conversion from MRD-positive to MRD-negative disease, but CYNK-001 cells were present in both the peripheral blood and bone marrow.

“The absence of DLT to date in the phase 1 trial enables us to continue with our scheduled dose escalation and to expand the trial to include patients with [relapsed/refractory] AML,” said Robert J. Hariri, MD, PhD, founder, chairman, and CEO of Celularity. “In addition, the demonstrated ability to deliver a total [natural killer] cell dose of 5.4 billion cells in the outpatient setting without DLT and the observation of achieving a conversion from an MRD-positive to MRD-negative state on bone marrow examination with CYNK-001 cells persisting in bone marrow and blood at 28 days after day 0 infusion, is compelling and supports our trial dose escalation and indication expansion.”

To date, no DLTs have been observed at any of the dose levels, including the total dose levels of 1.8 billion, 3.6 billion, and 5.4 billion CYNK-001 cells on days 0, 7, and 14, respectively, the company noted.

Celularity is developing off-the-shelf allogeneic therapies that are derived from postpartum human placenta. CYNK-001 is being investigated in solid and hematologic malignancies, as well as infectious diseases. The cryopreserved allogeneic off-the-shelf cell therapy is enriched for CD56+/CD3– NK cells that are expanded from human placental CD34+ cells.

Those who have any significant medical conditions that would prevent them from participating on the trial, laboratory abnormalities, bi-phenotypic acute leukemia, acute promyelocytic leukemia, inadequate organ function, autoimmune disease, and uncontrolled graft-vs-host disease or GVHD requiring corticosteroids, among other factors, were excluded from enrollment.

In their announcement, Celularity noted that it intends to continue dose escalation in the MRD indication to a total 9.0 billion CYNK-001 cells in addition to expanding the study to include those with relapsed/refractory AML.

To enhance the persistence of CYNK-001 therapy, the trial’s expansion arms of MRD and relapsed/refractory AML will comprise an augmented lymphodepletion protocol of 3600 mg of cyclophosphamide and 120 mg of fludarabine given over the course of 4 days compared with 900 mg of cyclophosphamide and 75 mg of fludarabine over 3 days. The dosing schedule analysis is used as a method to increase post-lymphodepletion interleukin (IL)-15 levels and to also add subcutaneous IL-2.

1. Celularity announces expansion of human placental hematopoietic stem cell derived natural killer cells (CYNK-001) phase 1 trial in patients with acute myeloid leukemia. News release. Celularity. June 29, 2021. Accessed June 29, 2021.

2. Natural killer cell (CYNK-001) infusions in adults with AML (CYNK001AML01). ClinicalTrials.gov. Updated March 2, 2021. Accessed June 29, 2021. 

Conversion from MRD positivity to MRD-negative disease in a high-dose patient prompted the expansion of the trial population. 

Celularity Expands Natural Killer Cell Therapy Trial to Relapsed/Refractory AML Following Patient Conversion

Treatment with the allogeneic CAR T-cell product ALLO-501A elicited encouraging signals of clinical activity when used with ALLO-647 lymphodepletion in patients with relapsed/refractory large B-cell lymphoma (LBCL) who did not previously receive autologous CAR T-cell therapy, according to findings from the phase 1/2 ALPHA2 study (NCT04416984) presented during the 2021 ASCO Annual Meeting.

Data showed that the objective response rate (ORR) with ALLO-501A in all patients (n = 9) was 56% (n = 5; 95% CI, 21%-86%), which included a 44% (n = 4; 95% CI, 14%-79%) complete response (CR) rate.

Specifically, in those who received ALLO-501A at the second dose level of 120 x 10

 CAR T cells (n = 4), the ORR was 50% (95% CI, 7%-93%) and both responses were CRs. For those who received ALLO-501A as a consolidation treatment (n = 5), the ORR was 60% (95% CI, 15%-95%) and the CR rate was 40% (95% CI, 5%-85%).

“Three patients had sufficient follow-up time to evaluate response after consolidation,” said Frederick L. Locke, MD, lead study author, vice chair of the Department of Blood and Marrow Transplant and Cellular Immunotherapy, and program co-leader of Immuno-Oncology at Moffitt Cancer Center, in a virtual presentation during the meeting. “Two out of 2 demonstrated responses deepening to CR by month 2, with the third maintaining a CR.”

Allogeneic CAR T-cell therapy has been identified as a method to address logistical and manufacturing challenges of autologous CAR T-cell products.

ALLO-501, an anti-CD19 CAR T-cell product, has rituximab (Rituxan) recognition domains. Prior data have demonstrated that ALLO-501 supported the clinical development of ALLO-501A, which is an allogeneic CAR T-cell therapy that excludes rituximab recognition domains.

ALLO-501A utilizes TALEN gene editing to disrupt the TCRα constant gene, which may reduce the risk of graft-vs-host disease (GVHD). Additionally, edited CD52 may permit the use of ALLO-647, a humanized anti-CD52 monoclonal antibody, to selectively deplete host T cells.

Previously, ALLO-501 produced deep responses in 32 patients with relapsed/refractory non-Hodgkin lymphoma in the phase 1 ALPHA trial (NCT03939026), with a 75% ORR (95% CI, 57%-89%) and a CR rate of 47% (95% CI, 29%-65%). In patients with follicular lymphoma (n = 21), the ORR was 81% (95% CI, 58%-95%) and the CR rate was 48% (95% CI, 26%-70%). In those with LBCL (n = 11), the ORR was 64% (95% CI, 31%-89%) and the CR rate was 46% (95% CI, 17%-77%). The longest ongoing remission persisted for at least 1 year, as of the patient’s last scan.

Additionally, the overall treatment failure-free survival rate (TFFS) at 6 months in all 32 patients was 63% (95% CI, 42%-78%). After the initial infusion, the 6-month CR rate was 29%; in those with follicular lymphoma and LBCL, the 6-month CR rates were 24% and 36%, respectively.

Among all autologous CAR T-cell therapy–naïve patients who achieved a CR, 3 patients remain in ongoing CR. The duration of response (DOR) in these patients is 5.1 months, while it was 11.1 months and 11.2 months in the follicular lymphoma and LBCL subgroups. In patients with follicular lymphoma and LBCL, the 1-year OS rates were 63% and 57%, respectively.

In the single-arm, open-label ALPHA2 study, investigators sought to determine whether ALLO-501A mirrored the efficacy results observed with ALLO-501 in the ALPHA trial.

In the study, ALLO-501 was examined in non-human leukocyte antigen–matched patients with relapsed/refractory LBCL, DLBCL, transformed follicular lymphoma, transformed marginal zone lymphoma (MZL), primary mediastinal B-cell lymphoma (PMBCL), and grade 3B follicular lymphoma.

Patients had to have received 2 or more prior lines of therapy, which included an anthracycline and anti-CD20 monoclonal antibody. The product was administered at the following doses: 40 x 106 (dose level 1 [DL1]; n = 1), 120 x 10

 (DL2; n = 5), and consolidation at 120 x 10

Retreatment was permitted for progressive disease or stable disease (SD) with suboptimal CAR T-cell expansion. The study was recently amended to include a note that patients who had SD or better at day 28 received consolidation therapy with an additional 30-mg dose of ALLO-647, making a total dose of 90 mg, and cell infusion of ALLO-501A.

The primary end point of the trial was safety, tolerability, and cell kinetics of ALLO-501A following lymphodepletion; secondary end points comprised investigator-assessed ORR, as well as cell kinetics of ALLO-501A.

Of the 13 patients enrolled, the mean age was 55 years; 39% had stage IV disease, 69% of patients had an ECOG performance status of 1, and 69% had a baseline lactate dehydrogenase level that was greater than the upper limit of normal. Forty-six percent of patients had an International Prognostic Index of 3 or higher, and the mean number of prior regimens received was 3. Moreover, 31% of patients had previously received an anti-CD19 treatment. Fifty-four percent of patients had germinal center B type and 46% had double- or triple-hit lymphoma.

In the consolidation arm, a second dose of ALLO-647 and cell infusion was to be administered. No cases of cytokine release syndrome (CRS), immune effector cell–associated neurotoxicity syndrome (ICANS), dose-limiting toxicities, or dose reductions were reported, nor were any related serious adverse effects (AEs). Regarding AEs of special interest, 1 case of grade 3 or higher CRS was reported at the 40 x 106 CAR T-cell dose.

In the safety analysis set (n = 13), 10 treatment-emergent AEs occurred. The most common AEs reported with the product were neutropenia (n = 9), leukopenia (n = 8), lymphopenia (n = 7), thrombocytopenia (n = 6), and anemia (n = 5).

Potential benefits of consolidation dosing were suggested with in vivo expansion of CAR T cells following the second infusion of ALLO-501A, Locke added.

Across both the ALPHA and ALPHA2 trials, ALLO-501 and ALLO-501A in combination with ALLO-647 lymphodepletion were well tolerated, with no GVHD, 1 event AE each of grade 3 ICANS and grade 3 CRS.

“[These data include] patients who were treated with either 1 or 2 doses, suggesting that the safety profile with consolidative dosing was also tolerable,” Locke concluded. “Redosing at the time of disease progression, or up-front consolidation, can be safely administered with emerging evidence of meaningful clinical benefit.”

Locke FL, Malik S, Tees MT, et al. First-in-human data of ALLO-501A, an allogeneic chimeric antigen receptor (CAR) T-cell therapy and ALLO-647 in relapsed/refractory large B-cell lymphoma (R/R LBCL): ALPHA2 study. 

. 2021;39(suppl 15):2529. doi:10.1200/JCO.2021.39.15_suppl.2529

Treatment with the allogeneic CAR T-cell product ALLO-501A elicited encouraging signals of clinical activity when used with ALLO-647 lymphodepletion in patients with relapsed/refractory large B-cell lymphoma who did not previously receive autologous CAR T-cell therapy. 

ALLO-501A Plus ALLO-647 Shows Promising CR Rate in Large B-Cell Lymphoma

The FDA granted a Regenerative Medicine Advanced Therapy (RMAT) designation to the allogeneic chimeric antigen receptor (CAR) T-cell therapy as a potential treatment for patients with relapsed/refractory multiple myeloma, according to Allogene Therapeutics, the developer of the off-the-shelf treatment.

“RMAT designation was granted based on our encouraging initial clinical experience in heavily pretreated patients. ALLO-715 demonstrated for the first time that an allogeneic CAR T therapy directed at BCMA can achieve deep clinical responses while eliminating the need for bridging therapy and delays associated with autologous CAR T manufacturing,” said Rafael Amado, MD, executive vice president of Research and Development, and chief medical officer at Allogene Therapeutics. “We look forward to completing the UNIVERSAL study and working closely with the FDA as we seek to rapidly advance this important therapeutic alternative to patients with advanced multiple myeloma.”

RMAT designation is designed to accelerate the development and review processes for a variety of investigational agents, which includes the benefits of fast track and breakthrough designations. The FDA deems eligibility for RMAT designation for an investigational cell therapy if it is planned to treat, modify, reverse, or cure serious or life-threatening diseases. The treatment needs to also provide preliminary clinical data showcasing its potential to address unmet medical needs for that disease. Allogene Therapeutics also noted RMAT benefits include early discussions with FDA that could be focused on potential surrogate or intermediate end points, as well as methods that could meet post approval requirements.

The FDA granted the designation based on the potential of ALLO-715, which is aimed to target an unmet need for patients who have failed available treatments for multiple myeloma. ALLO-715 features a human-derived single-chain variable fragment anti-BCMA cell with a 4-1BB costimulatory domain.

Most recently, first-in-human findings of ALLO-715 from the ongoing phase 1 UNIVERSAL study (NCT04093596) were presented during the 2020 ASH Annual Meeting.

UNIVERSAL is being conducted at 11 centers in the United States, and is recruiting patients with multiple myeloma who are refractory to their last treatment and who have received 3 or more prior therapies, including an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. An ECOG performance status score of 0 or 1 is required.

In the dose-escalation portion of the study, ALLO-715 is being evaluated as a single infusion across 4 doses: 40 x 106, 160 x 106, 320 x 106, or 480 x 106 CARs. Lymphodepletion regimens are comprised of fludarabine (F; 30 mg/m2 daily) plus cyclophosphamide (C; 300 mg/m2 daily) given on 3 days with the monoclonal antibody ALLO-647 (A; 13-30 mg x 3 days; FCA) or cyclophosphamide plus ALLO-647 (CA).

At the time of the 2020 ASH Annual Meeting presentation, 35 patients were enrolled. Four patients were ineligible due to organ failure from disease progression. Of the 31 patients who were in the safety population, the median age was 65 years (range, 46-76). Nearly half of the patients (48%) have high-risk cytogenetics and 23% had extramedullary disease. The efficacy population at data cutoff on October 30, 2020 included 26 patients across the 4 dosing levels, with a median follow-up of 3.2 months.

Results showed that, at the 320 x 106 CAR cells dose plus the ALLO-647 lymphodepletion regimen, the therapy elicited a 60% overall response rate (ORR; n = 6/10) responses, which included a very good partial-plus response (VGPR+) in 4 patients (40%).

Responses varied across the other dosing cohorts and lymphodepleting regimens. No responses were observed among 3 patients each who received CARs at 40 x 106 with FCA or 160 x 106 with CA, both with low-dose ALLO-647. The ORRs were 50% in 4 patients who received CARs at 160 x 106 with low–ALLO-647 FCA; 33% in 3 at 480 x 106 with low–ALLO-647 FCA; and 67% in 3 at 320 x 106 with low–ALLO-647 CA.

Regarding the safety population (n = 31), most adverse effects occurred at grades 1/2 severity, which included cytokine release syndrome (CRS) in 14 patients (45%) and infusion-related reactions to ALLO-647 in 7 (23%). Tocilizumab (Actemra) was used in 19% and steroids in 10% of these patients to manage CRS.

All-grade infections occurred in 13 patients (42%), including grade 3 events in 4 (13%). One patient (3%) died from a presumed fungal pneumonia related to progressive disease and the CA conditioning regimen but unrelated to ALLO-715. Neither neurotoxicity nor GVHD were reported.

Allogene Therapeutics announces FDA Regenerative Medicine Advanced Therapy (RMAT) Designation granted to ALLO-715, an AlloCAR T™ cell therapy in development for relapsed/refractory multiple myeloma. News release. Allogene Therapeutics. April 21, 2021. Accessed April 21, 2021. 

Mailankody S, Matous JV, Liedtke M, et al. Universal: an allogeneic first-in-human study of the anti-Bcma ALLO-715 and the Anti-CD52 ALLO-647 in relapsed/refractory multiple myeloma. Presented at: 2020 ASH Annual Meeting and Exposition; December 5-8, 2020; virtual. Abstract 129.

The FDA granted a Regenerative Medicine Advanced Therapy designation to the allogeneic chimeric antigen receptor T-cell therapy as a potential treatment for patients with relapsed/refractory multiple myeloma.

FDA Grants RMAT Designation to ALLO-715 for Relapsed/Refractory Multiple Myeloma 

Cord blood-derived allogeneic natural killer (cbNK) cells pre-complexed with the innate cell engager AFM13 demonstrated an objective response rate (ORR) of 100% in adult patients with CD30-positive, relapsed/refractory Hodgkin lymphoma, according to early findings from a phase 1 trial presented at the 

American Association for Cancer Research Annual Meeting 2021

Data showed that the first 4 patients all responded to the therapy, with 2 complete responses (CRs) and 2 partial responses (PRs). Regarding safety, no cytokine release syndrome, neurotoxicity syndrome, or graft-vs-host disease was observed.

“There remains a high unmet need for effective treatments in relapsed/refractory CD30-positive lymphomas. We are encouraged by the data generated from the first patients treated with cbNK cells pre-complexed with AFM13,” Katy Rezvani, MD, PhD, professor of stem cell transplantation and cellular therapy at The University of Texas MD Anderson Cancer Center, who presented the data as part of the Major Symposia and Advances sessions during the conference, said in a statement. “The results suggest this combination is facilitating clinical responses with minimal toxicity, warranting further study as we continue to explore novel cell therapies for our patients.”

AFM13 is described as a first-in-class innate cell engager that activates the immune system and targets CD30-positive hematologic cancers; AFM13 induces specific and selective killing of CD30-positive cells. The therapy is also being tested as a single agent in the ongoing, registration-directed REDIRECT study (NCT04101331) in patients with relapsed/refractory peripheral T-cell lymphoma or transformed mycosis fungoides.

In the investigator-sponsored, dose-escalation, phase 1 trial in Hodgkin lymphoma, researchers are exploring AFM13 in combination with cbNK cells in patients with recurrent/refractory CD30-positive lymphomas. Patients are first given preconditioning with cyclophosphamide at 300 mg/m

The primary end point is safety, efficacy, and determine the recommended phase 2 dose. In all cohorts, the dose of pre-complexed NK cells with AFM13 is followed by 200 mg of AFM13 alone for 3 weeks. All patients were evaluated for dose-limiting toxicities and responses on day 28.

As of March 31, 2021, 3 patients were dosed with 2 cycles of therapy in dose cohort 1 (1 x 10

 of AFM13-cbNK/kg) and 1 patient received a single cycle of treatment at dose cohort 2 (1 x 10

The patient demographics at dose cohort 1 was as follows:

A 43-year-old male with Hodgkin lymphoma who had underwent 4 lines of treatment (doxorubicin, bleomycin, vinblastine, and dacarbazine [ABVD]; ifosfamide, carboplatin and etoposide [ICE]; brentuximab vedotin [Adcetris], and nivolumab [Opdivo] plus ruxolitinib [Jakafi])

A 31-year-old male with Hodgkin lymphoma with 14 prior lines of therapy (ABVD, brentuximab vedotin, HDAC inhibitor/PI3K inhibitor, pembrolizumab [Keytruda], nivolumab, allogeneic hematopoietic stem cell transplant [HSCT], hypercytoxan, ibrutinib [Imbruvica], niraparib [Zejula], bendamustine, everolimus [Afinitor])

A 53-year-old female with Hodgkin lymphoma who previously received 5 lines of therapy (ABVD, ICE, brentuximab vedotin, nivolumab, and gemcitabine/oxaliplatin)

Dose cohort 2, which is ongoing, currently includes a 26-year-old male with Hodgkin lymphoma who underwent 9 lines of treatment (ABVD, ICE and brentuximab vedotin, radiation, nivolumab, CD30-based CAR T-cell therapy, TTI-622, brentuximab vedotin/bendamustine, allogeneic HSCT, brentuximab vedotin/bendamustine with brentuximab vedotin maintenance). Three patients are expected to be enrolled in this cohort overall.

Responses are assessed by the Lymphoma Response to Immunomodulatory Therapy Criteria.

Preclinical findings of this therapy, which Rezvani highlighted in the AACR presentation, showed that interleukin (IL)-12, IL-15, and IL-18 pre-activated and ex-vivo–expanded cbNK cells can develop properties similar to chimeric antigen receptor–like properties when precomplexed with AFM13. Moreover, compared with cells that were only expanded, the IL-12/15/18 pre-activated and ex-vivo–expanded cbNK cells showed upregulation of genes that were related to JAK-STAT signaling and interferon gamma response.

AFM13 was also found to be retained on surface NK cells following pre-complexing, which endows them with CAR-like properties against CD30–positive Karpas 299. Furthermore, AFM13-complexed CAR-like cbNK cells display heightened ability to control tumors in a xenograft mouse model of CD30-positive T-cell lymphoma in vivo.

Currently, the phase 1 study is enrolling patients onto dose cohort 2 with additional data reported later this year.

“We are encouraged by the initial safety and efficacy data from this groundbreaking first-in-human study. The finding of an objective response rate of 100% amongst our first 4 patients enrolled is impressive,” Andreas Harstrick, MD, chief medical officer of Affimed, said in a prepared statement. “These initial results indicate AFM13 may have the potential to help NK cells target and destroy cancer cells. We plan to continue to develop and customize approaches that leverage the unique and differentiating features of our ICE molecules in combination with adoptive NK cell transfer to provide options for treating a variety of hematologic and solid tumors.”

1. Affimed announces presentation at AACR highlighting initial data from phase 1 study of cord blood-derived natural killer cells pre-complexed with innate cell engager AFM13. News release. AffiMed. April 9, 2021. Accessed April 12, 2021. 

2. Rezvani K. CAR NK cells: a drive to the future of cell therapy. Presented at: AACR Annual Meeting 2021; April 10-15, 2021; Virtual.

In a phase 1 study of the innate cell engager AFM13 pre-complexed with NK cells, all 4 patients with CD30-positive, relapsed/refractory Hodgkin lymphoma treated with the therapy achieved at least a partial response.

NK Cell/AFM13 Complex Elicits 100% Response Rate for Hodgkin Lymphoma

The FDA has approved idecabtagene vicleucel (ide-cel; Abecma) as the first BCMA-directed chimeric antigen receptor (CAR) T-cell therapy for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. 

The approval is based on findings from the pivotal, phase 2 KarMMA trial, in which ide-cel elicited an overall response rate (ORR) of 72% (95% CI, 62%-81%) and a stringent complete response (sCR) rate of 28% (95% CI, 19%-38%) in an efficacy evaluable population (n = 100) of patients with relapsed/refractory myeloma who had received at least 4 prior treatments. 

Ide-cel is approved as a one-time infusion with a recommended dose range of 300 to 460 x 10

“In the KarMMa study, ide-cel elicited rapid responses in the majority of patients, and these deep and durable responses were observed in patients with triple-class exposed and refractory multiple myeloma,” said Nikhil C. Munshi, MD, associate director of the Jerome Lipper Multiple Myeloma Center at Dana-Farber Cancer Institute. “As a treating physician, I often work with patients with relapsed or refractory multiple myeloma who are in critical need of new therapies. Now, with the approval of ide-cel as the first anti-BCMA CAR T cell therapy, we are excited to finally be able to offer patients a new, effective personalized treatment option that is delivered through a single infusion.”

KarMMA included a total of 128 patients with relapsed/refractory multiple myeloma who had received at least 3 previous therapies, including an IMiD, a PI, and an anti-CD39 antibody. The median age of the participants was 61 years, and 35% of patients had high-risk cytogenetics. About half of patients, or 51%, had high tumor burden, while 39% had extramedullary disease and 85% had 50% or higher tumor BCMA expression. Forty-five percent of participants had an ECOG performance status of 0, 53% had a status of 1, and 2% had a status of 2. R-ISS stage disease was I in 11% of patients, II in 70% of patients, and III in 16%. Overall, participants had received a median of 6 previous treatments (range, 3-16).

The majority of patients, or 94%, had undergone 1 previous autologous stem cell transplant; 34% had undergone more than 1 of these procedures. Moreover, 88% of participants had been given bridging therapies during CAR T-cell manufacturing, but only 4% responded to that treatment. Ninety-four percent of patients proved to be refractory to anti-CD38 antibodies, and the majority, or 84%, were determined to be triple refractory.

In the trial, participants were given at the following CAR T cell doses: 150 x 10

 (n = 4), 200 x 106 (n = 70), or 450 x 10

 (n = 54). The median follow-up was 18 months for the first dosing cohort, 15.8 months in the second, and 12.4 months in the third. Across the entire study population, the median follow-up was 13.3 months. The primary end point of the trial was ORR, and key secondary end points were comprised of CR, DOR, PFS, overall survival (OS), and quality of life.

The FDA has approved idecabtagene vicleucel as the first BCMA-directed CAR T-cell therapy for patients with relapsed/refractory multiple myeloma after 4 or more prior lines of therapy, including an immunomodulatory agent, a proteasome inhibitor, and an anti-CD38 monoclonal antibody. 








