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Novel Targets and Strategic Sequencing: The Evolving Landscape of T-Cell Redirection Therapies in Multiple Myeloma

OncologyCAR-T
  • CAR T-cell therapies and bispecific antibodies targeting BCMA and GPRC5D are transforming multiple myeloma treatment, with ciltacabtagene autoleucel showing unprecedented efficacy with a median PFS of 34.9 months in heavily pretreated patients.
  • Disease progression rate is a critical factor in therapy selection, with rapidly progressing patients better suited for "off-the-shelf" bispecific antibodies, while patients with indolent disease may benefit more from CAR T-cell therapies despite longer manufacturing times.
  • Strategic sequencing of therapies is crucial, as prior BCMA-directed bispecific antibody treatment significantly reduces the efficacy of subsequent BCMA-targeted CAR T-cell therapy, highlighting the importance of preserving T-cell fitness and considering antigen loss.

Safety and Efficacy of Anti-BCMA/GPRC5D CAR-T Cell Therapy in Treating Relapsed and Refractory Multiple Myeloma(rr/MM)

NCT05509530RecruitingPhase 2
Xuzhou Medical University
Posted 5/1/2022

A Study of CAR-T Cells Targeting Both BCMA and GPRC5D in Treatment of Relapsed or Refractory Multiple Myeloma

NCT05325801Not Yet RecruitingPhase 1
Zhejiang University
Posted 4/1/2022

A Study of CAR-T Cells Targeting GPRC5D in the Treatment of r/r Multiple Myeloma

NCT05016778Active, Not RecruitingEarly Phase 1
Zhejiang University
Posted 6/8/2021

A Study of MCARH109 and MCARH125 in People With Multiple Myeloma

NCT05431608Active, Not RecruitingPhase 1
Memorial Sloan Kettering Cancer Center
Posted 6/20/2022

A Study of Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (DVRd) Followed by Ciltacabtagene Autoleucel Versus Daratumumab, Bortezomib, Lenalidomide and Dexamethasone (DVRd) Followed by Autologous Stem Cell Transplant (ASCT) in Participants With Newly Diagnosed Multiple Myeloma

NCT05257083Active, Not RecruitingPhase 3
Stichting European Myeloma Network
Posted 10/10/2023

A Study of JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against B-cell Maturation Antigen (BCMA) in Participants With Multiple Myeloma

NCT04133636RecruitingPhase 2
Janssen Research & Development, LLC
Posted 11/7/2019

A Study of Talquetamab in Participants With Relapsed or Refractory Multiple Myeloma

NCT04634552RecruitingPhase 2
Janssen Research & Development, LLC
Posted 2/1/2021

Dose Escalation Study of Talquetamab in Participants With Relapsed or Refractory Multiple Myeloma

NCT03399799Active, Not RecruitingPhase 1
Janssen Research & Development, LLC
Posted 12/16/2017

MCARH109 Chimeric Antigen Receptor (CAR) Modified T Cells for the Treatment of Multiple Myeloma

NCT04555551Active, Not RecruitingPhase 1
Memorial Sloan Kettering Cancer Center
Posted 9/8/2020

A Study of JNJ-68284528, a Chimeric Antigen Receptor T Cell (CAR-T) Therapy Directed Against B-Cell Maturation Antigen (BCMA) in Participants With Relapsed or Refractory Multiple Myeloma

NCT03548207CompletedPhase 1
Janssen Research & Development, LLC
Posted 6/29/2018

MagnetisMM-3: Study Of Elranatamab (PF-06863135) Monotherapy in Participants With Multiple Myeloma Who Are Refractory to at Least One PI, One IMiD and One Anti-CD38 mAb

NCT04649359Active, Not RecruitingPhase 2
Pfizer
Posted 2/2/2021

A Study of Teclistamab in Participants With Relapsed or Refractory Multiple Myeloma

NCT04557098Active, Not RecruitingPhase 2
Janssen Research & Development, LLC
Posted 9/17/2020

A Study Comparing JNJ-68284528, a CAR-T Therapy Directed Against B-cell Maturation Antigen (BCMA), Versus Pomalidomide, Bortezomib and Dexamethasone (PVd) or Daratumumab, Pomalidomide and Dexamethasone (DPd) in Participants With Relapsed and Lenalidomide-Refractory Multiple Myeloma

NCT04181827Active, Not RecruitingPhase 3
Janssen Research & Development, LLC
Posted 6/12/2020

Efficacy and Safety Study of bb2121 in Subjects With Relapsed and Refractory Multiple Myeloma

NCT03361748CompletedPhase 2
Celgene
Posted 12/13/2017

Safety and Efficacy of ALLO-715 BCMA Allogenic CAR T Cells in in Adults With Relapsed or Refractory Multiple Myeloma (UNIVERSAL)

NCT04093596Active, Not RecruitingPhase 1
Allogene Therapeutics
Posted 9/23/2019

A Study of the Combination of Talquetamab and Teclistamab in Participants With Relapsed or Refractory Multiple Myeloma

NCT04586426Active, Not RecruitingPhase 1
Janssen Research & Development, LLC
Posted 12/15/2020

Efficacy and Safety Study of bb2121 Versus Standard Regimens in Subjects With Relapsed and Refractory Multiple Myeloma (RRMM)

NCT03651128Active, Not RecruitingPhase 3
Celgene
Posted 4/16/2019

A Study of Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed by Cilta-cel, a CAR-T Therapy Directed Against BCMA Versus VRd Followed by Lenalidomide and Dexamethasone (Rd) Therapy in Participants With Newly Diagnosed Multiple Myeloma for Whom ASCT is Not Planned as Initial Therapy

NCT04923893Active, Not RecruitingPhase 3
Janssen Research & Development, LLC
Posted 8/19/2021

Bispecific T-Cell Engagers Show Promise as Later-Line Therapies for Relapsed/Refractory DLBCL

CAR-TDrug ApprovalOncology
  • Two bispecific T-cell engagers, epcoritamab-bysp and glofitamab-gxbm, received FDA accelerated approval in 2023 for relapsed/refractory diffuse large B-cell lymphoma, offering new treatment options for heavily pretreated patients.
  • Both agents demonstrate remarkable activity with overall response rates above 50-60% and complete response rates around 40% in patients with CAR T-cell therapy failure, addressing a significant unmet medical need.
  • Epcoritamab offers convenient subcutaneous administration in outpatient settings with manageable cytokine release syndrome rates below 3%, while glofitamab provides fixed-duration therapy with durable responses lasting over one year after treatment completion.
  • These bispecific antibodies may challenge the paradigm that CAR T-cell therapy is the only curative option for relapsed/refractory patients, with emerging data suggesting potential for long-term disease control.

A Dose Escalation Study of Glofitamab (RO7082859) as a Single Agent and in Combination With Obinutuzumab, Administered After a Fixed, Single Pre-treatment Dose of Obinutuzumab in Participants With Relapsed/Refractory B-cell Non-hodgkin's Lymphoma

NCT03075696RecruitingPhase 1
Hoffmann-La Roche
Posted 2/21/2017

First-in-Human (FIH) Trial in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma

NCT03625037Active, Not RecruitingPhase 1
Genmab
Posted 6/26/2018

Samuraciclib Shows Promise in Advanced Breast Cancer Patients After CDK4/6 Inhibitor Failure

OncologyTargeted TherapyPrecision Medicine
  • Phase I clinical trials demonstrate samuraciclib, a selective CDK7 inhibitor, has an acceptable safety profile with manageable gastrointestinal side effects and shows clinical activity in various advanced solid tumors.
  • In HR+/HER2- breast cancer patients who progressed on CDK4/6 inhibitors, the combination of samuraciclib with fulvestrant achieved a clinical benefit rate of 36% and median progression-free survival of 3.7 months.
  • Exploratory analysis revealed patients without TP53 mutations had significantly longer progression-free survival (7.4 months vs 1.8 months), suggesting TP53 status may serve as a potential biomarker for treatment response.

Modular Study to Evaluate CT7001 Alone in Cancer Patients With Advanced Malignancies

NCT03363893CompletedPhase 1
Carrick Therapeutics Limited
Posted 11/14/2017

Avutometinib-Defactinib Combination Shows 45% Response Rate in Low-Grade Serous Ovarian Cancer

Targeted TherapyOncology
  • A phase II trial of avutometinib combined with defactinib demonstrated a 45% response rate in patients with advanced low-grade serous ovarian cancer, nearly twice as effective as current best treatments.
  • Patients with KRAS mutations showed particularly strong responses at 60%, while those without mutations still achieved a 29% response rate, both significantly higher than standard therapy response rates of 0-14%.
  • The dual RAF/MEK inhibitor combination proved over four times more effective than avutometinib alone, with previous phase I data showing an average progression-free survival of 23 months.
  • Low-grade serous ovarian cancer affects approximately 700 women annually in the UK and represents about 10% of all ovarian cancer cases, typically affecting younger women with poor response to conventional treatments.

Phase I Trial of Defactinib and VS-6766.

NCT03875820Active, Not RecruitingPhase 1
Institute of Cancer Research, United Kingdom
Posted 12/12/2017

Trametinib in Treating Patients With Recurrent or Progressive Low-Grade Ovarian Cancer or Peritoneal Cavity Cancer

NCT02101788Active, Not RecruitingPhase 2
National Cancer Institute (NCI)
Posted 2/27/2014

A Study of Avutometinib (VS-6766) V. Avutometinib (VS-6766) + Defactinib in Recurrent Low-Grade Serous Ovarian Cancer with and Without a KRAS Mutation

NCT04625270Active, Not RecruitingPhase 2
Verastem, Inc.
Posted 12/21/2020

A Study of MEK162 vs. Physician's Choice Chemotherapy in Patients With Low-grade Serous Ovarian, Fallopian Tube or Peritoneal Cancer

NCT01849874TerminatedPhase 3
Pfizer
Posted 6/27/2013

Vorasidenib Shows Promise as First Targeted Therapy for IDH-Mutant Low-Grade Gliomas

Targeted TherapyDrug ApprovalOncology
  • Vorasidenib, the first targeted therapy developed specifically for brain cancer, more than doubled progression-free survival in patients with recurrent grade 2 glioma carrying IDH1/IDH2 mutations, extending the time without disease progression from 11.1 months to 27.7 months.
  • The international INDIGO trial involving 331 patients demonstrated that vorasidenib delayed the need for chemotherapy and radiation by nearly 17 months compared to placebo, with 85.6% of patients going 18 months before requiring next treatment.
  • The drug showed excellent tolerability with limited adverse effects, offering a new treatment option for younger patients typically in their 30s and 40s who face cognitive deficits from standard radiation and chemotherapy treatments.
  • Results from this phase 3 study, published in the New England Journal of Medicine and presented at ASCO, are expected to establish a new standard of care for IDH-mutant low-grade gliomas pending FDA approval.

FDA Approves Two Bispecific T-Cell Engagers for Relapsed/Refractory B-Cell Lymphomas

Drug ApprovalOncology
  • The FDA has granted accelerated approval to epcoritamab-bysp (Epkinly), the first T-cell engaging bispecific antibody for relapsed/refractory diffuse large B-cell lymphoma after two or more lines of systemic therapy.
  • Epcoritamab demonstrated a 61% overall response rate with a 38% complete response rate in the EPCORE NHL-1 trial, with a median duration of response of 15.6 months.
  • The FDA also approved glofitamab-gxbm (Columvi), another CD20/CD3-targeted bispecific T-cell engager, showing a 56% overall response rate and 43% complete response rate in clinical trials.
  • Both therapies carry boxed warnings for serious immune-related adverse reactions including cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome.

Study to Investigate the Safety and Tolerability of Odronextamab in Patients With CD20+ B-Cell Malignancies

NCT02290951CompletedPhase 1
Regeneron Pharmaceuticals
Posted 1/9/2015

First-in-Human (FIH) Trial in Patients With Relapsed, Progressive or Refractory B-Cell Lymphoma

NCT03625037Active, Not RecruitingPhase 1
Genmab
Posted 6/26/2018

A Study to Assess the Anti-Tumor Activity and Safety of Odronextamab in Adult Patients With B-cell Non-Hodgkin Lymphoma Who Have Been Previously Treated With Other Cancer Therapies

NCT03888105RecruitingPhase 2
Regeneron Pharmaceuticals
Posted 11/13/2019

Radiopharm Theranostics Expands Partnership with GenesisCare for Phase I Radiopharmaceutical Trials in Australia

Monoclonal AntibodyOncology
  • Radiopharm Theranostics has expanded its strategic research collaboration with GenesisCare to conduct Phase I trials of three radiopharmaceutical candidates targeting hard-to-treat cancers in Australia.
  • The trials will evaluate a PDL-1 targeting nano-mAb for non-small cell lung cancer, a PTPu targeting peptide for brain tumors, and a PSA targeting antibody for prostate cancer.
  • Radiopharmaceuticals deliver small doses of radiation to specifically targeted cells for therapeutic or diagnostic purposes, offering new hope to patients who have exhausted other treatment options.
  • The two-year collaboration leverages GenesisCare's contract research organization capabilities across its 440+ locations in Australia, UK, US, and Spain.

Revumenib Shows Promise in Phase 1 Trial for KMT2A-Rearranged and NPM1-Mutated Acute Leukemia

OncologyTargeted Therapy
  • Revumenib, a first-in-class menin inhibitor, demonstrated a 30% complete remission rate in heavily pretreated patients with KMT2A-rearranged or NPM1-mutated acute leukemia, with 78% achieving undetectable measurable residual disease.
  • The oral therapy works by disrupting the menin-KMT2A interaction, downregulating key leukemogenic genes and promoting differentiation of leukemic cells, addressing a critical unmet need for these poor-prognosis genetic subtypes.
  • While QT interval prolongation was the most common treatment-related adverse event (53%), the phase 1 trial established recommended phase 2 dosing with manageable safety profile, supporting further development of this targeted therapy.

BriaCell Advances Pivotal Study for Bria-IMT in Metastatic Breast Cancer Following Positive FDA Feedback

Oncology
  • BriaCell Therapeutics has received positive FDA feedback for its pivotal study of Bria-IMT in combination with a checkpoint inhibitor for advanced metastatic breast cancer, potentially accelerating commercialization.
  • The FDA has agreed on the eligible patient population—breast cancer patients who have failed available approved therapies—and the primary endpoint of survival improvement compared to physician's choice of treatment.
  • BriaCell is also preparing to launch its Bria-OTS personalized treatment program, which matches patients' HLA type with pre-manufactured cells, with dosing expected to begin in the first half of 2023.

BDR Pharmaceutical Launches First Generic Apalutamide in India for Prostate Cancer Treatment

Oncology
  • BDR Pharmaceutical has launched India's first generic version of apalutamide (brand name Apatide) for treating metastatic castration-sensitive and non-metastatic castration-resistant prostate cancer.
  • The generic drug is priced at one-third the cost of the innovator brand, with 60 tablets costing Rs 22,500 and 120 tablets costing Rs 45,000.
  • Clinical data from the SPARTAN trial showed apalutamide plus androgen-deprivation therapy reduced disease progression risk by 71% and improved median progression-free survival from 14.7 to 40.5 months.
  • The launch addresses India's growing prostate cancer burden, where it ranks as the second most common cancer and sixth leading cause of cancer deaths among men.

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