FDA Places Clinical Hold on KEYNOTE-B79 Trial Examining CAR T-cell Therapy CYAD-101 in Metastatic CRC

US FDA

The FDA has placed a clinical hold on the phase 1b CYAD-101-002 trial (KEYNOTE-B79; NCT04991948), which is examining the safety and clinical activity of the investigational CAR T-cell therapy CYAD-101 given concurrently with FOLFOX (leucovorin, 5-fluorouracil, and oxaliplatin) and followed by pembrolizumab (Keytruda) in patients with unresectable metastatic colorectal cancer (mCRC).¹

The hold was put in place because of insufficient information to evaluate risk to study participants, according to a press release issued by Celyad Oncology, the product developer.

Previously, on February 28, 2022, the clinical-stage biotechnology company announced that they decided to voluntarily pause the trial to further examine reports of 2 fatalities that occurred on the study that presented with similar pulmonary findings.² The company is in the process of investigating any similar events in additional patients treated on the study.

“Our primary commitment is to maintain patient safety, which is why we decided to place the trial on hold while we investigate these events,” Filippo Petti, chief executive officer of Celyad Oncology, stated in a prior press release. “We are working diligently to better understand these events. In 25 patients previously treated with CYAD-101 in the alloSHRINK phase 1 trial [NCT03692429], which evaluated the TIM-based investigational candidate for the treatment of advanced mCRC, no dose-limiting toxicities [DLTs] were reported. Lastly, we anticipate no impact on our shRNA-based candidates, including CYAD-211, [which is] currently under investigation for the treatment of multiple myeloma.”

CYAD-101 is an investigational, non-gene edited allogeneic CAR T-cell product that was engineered to co-express the chimeric antigen receptor based on NKG2D, which is expressed on natural killer cells that binds to NKG2DL that are expressed by a wide range of tumor cells and the inhibitory peptide TIM.³ TIM expression reduces signaling of the TCR complex by interfering with the CD3ζ component of the complex.

KEYNOTE-B79 enrolled patients with historically proven metastatic adenocarcinoma of the colon or rectum, an ECOG performance status of 0 or 1, and acceptable organ, hepatic, renal, pulmonary, and cardiac functions.⁴

Patients could not have received another investigational agent, device, or anticancer agent within 4 weeks of the first study treatment; filgrastim or similar growth factors within 7 days of the first study treatment; PD-1/PD-L1/PD-L2 agents or an agent directed to another stimulatory or co-inhibitory T-cell receptor; radiotherapy within 2 weeks before first study treatment; or a live vaccine within 30 days before first study treatment. Moreover, patients could not have a history of pneumonitis, or have undergone major surgery within 4 weeks before first study treatment.

The primary outcome measures of the early-phase trial included occurrence of DLTs and objective response rate.

In the phase 1 alloSHRINK study, investigators evaluated CYAD-101 in patients with refractory unresectable mCRC following FOLFOX preconditioning.5 A total of 15 patients received the CAR T-cell product at the following doses: 1 x 108, 3 x 108, or 1 x109 cells.

Preliminary data from the trial demonstrated that 2 patients achieved partial responses (PRs) with treatment, including 1 patient whose tumor harbored a KRAS mutation. Moreover, 9 patients had stable disease (SD), 7 of whom had SD for 3 months or longer. Regarding safety, no graft-versus-host disease was observed, nor were there any grade 3 or higher treatment-related toxicities. The recommended dose for further investigation was determined to be 1x109 CAR T cells/infusion.

Additional data presented during the 2021 Gastrointestinal Cancers Symposium showed that when CYAD-101 was given at the highest dose level (n = 9), evidence of tumor control per RECIST v1.1 criteria was observed in 6 patients. The median progression-free survival achieved with the CAR T-cell therapy was 3.94 months (range, 1.2-8.1), and the median overall survival was 10.58 months (range, 1.9-18.7).

Moreover, within patients who achieved SD or PR, investigators noted evidence of new T-cell clones entering the hyper-extended TCR repertoire following treatment. Additionally, an elevation of Luminex score was noted in a patient who had a durable PR following their first and second infusion of the CAR T-cell therapy.

Investigators concluded that their observations suggest that modulation of the endogenous immune response could be an important mechanism of action of CYAD-101 in this patient population. They plan to evaluate this further and confirm their observations in an ongoing expansion phase of the trial.

References

1. Celyad Oncology announces clinical hold of CYAD-101-002 phase 1b trial. News release. Celyad Oncology SA; March 2, 2022. Accessed March 2, 2022. https://bwnews.pr/3hzqpCV
2. Celyad Oncology announces voluntary pause of CYAD-101-002 phase 1b trial. News release. Celyad Oncology SA; February 28, 2022. Accessed March 2, 2022. https://bit.ly/3sAGXAZ
3. Celyad Oncology SA. Pipeline. Accessed March 2, 2022. https://bit.ly/3MhnKfy
4. Phase 1b study to evaluate the addition of a pembrolizumab treatment after treatment with CYAD-101 with a FOLFOX preconditioning in metastatic colorectal cancer patients. ClinicalTrials.gov. Updated August 5, 2021. Accessed March 2, 2022. https://clinicaltrials.gov/ct2/show/NCT04991948