Bristol-Myers Squibb (BMS) has acknowledged that the FDA has placed a partial clinical hold on three clinical trials investigating combination therapies based on its marketed cancer immunotherapy Opdivo® (nivolumab) in patients with relapsed or refractory multiple myeloma.

The FDA based its action on a conclusion that the risks outweighed the benefits for treatments that combined programmed cell death protein 1/programmed death-ligand 1 (PD-1/PD-L1) cancer immunotherapies with pomalidomide or lenalidomide, and possibly PD-1/PD-L1 treatments alone or with other combinations.

The agency’s conclusion came from findings from non-Opdivo combination-therapy studies, BMS said.

“BMS remains steadfast in our commitment to improve outcomes for patients with multiple myeloma, and will work closely with the FDA to address concerns,” the Company said yesterday in a statement.

Trials halted by the FDA include:

  • CheckMate-602, a Phase III trial assessing combinations of Opdivo, BMS’ Empliciti™ (elotuzumab), Celgene’s Pomalyst® (pomalidomide), and dexamethasone in relapsed and refractory multiple myeloma (NCT02726581).
  • CA204142, a Phase II, multiple-cohort study assessing Empliciti with Pomalyst and low-dose dexamethasone, and with Opdivo in patients with multiple myeloma relapsed or refractory to prior treatment with lenalidomide (NCT02612779).
  • CheckMate-039, a Phase I study to establish the tolerability of Opdivo and the combination of Opdivo and Janssen Biotech ’s [Johnson & Johnson] Darzalex® (daratumumab), with or without Pomalyst and dexamethasone, in subjects with relapsed or refractory multiple myeloma (NCT01592370).

Patients currently enrolled in the three trials can continue treatment if they are experiencing clinical benefit, BMS added, though no new patients will enroll in the studies.

The partial holds come two months after the agency placed clinical holds on three trials assessing combinations using Merck & Co.’s approved cancer immunotherapy Keytruda® (pembrolilzumab) to treat multiple myeloma.

The agency acted after the trials’ Data Monitoring Committee reviewed data and found more deaths among patients treated with Keytruda in two Phase III studies among the three halted by the FDA, KEYNOTE-183 and KEYNOTE-185. That finding prompted Merck to halt enrollment in both trials in June.


Scrutinizing Combo Trials After Deaths

In an August 31 statement, FDA Center for Drug Evaluation and Research Director Janet Woodcock, M.D., said the agency was working with developers of other PD-1/PD-L1 inhibitors to examine other combination trials assessing the candidates in blood cancers.

“The FDA will take appropriate action as warranted to ensure patients enrolled in these trials are protected and that doctors and clinical trial researchers understand the risks associated with this investigational use,” Dr. Woodcock stated.

Also on August 31, the FDA alerted healthcare professionals to risks associated with Keytruda in combination with dexamethasone and an immunomodulatory agent (lenalidomide or pomalidomide) for the treatment of patients with multiple myeloma, based on findings of a combined 78 reported deaths in KEYNOTE-183 and KEYNOTE-185.

KEYNOTE-183 was designed to assess the combination of Keytruda with Pomalyst and low-dose dexamethasone in patients with refractory or relapsed and refractory multiple myeloma. KEYNOTE-183 (NCT02576977) has an estimated enrollment of 300 patients, an estimated primary completion date of August 31, 2018, and an estimated study completion date of October 31, 2019, according to

“There were 29 deaths on the pembrolizumab-containing investigational arm and 21 deaths on the control arm” in KEYNOTE-183, the FDA told healthcare professionals.

KEYNOTE-185 was to study the combination of Keytruda with another Celgene-marketed cancer drug, Revlimid® (lenalidomide), and low-dose dexamethasone in newly diagnosed and treatment-naïve multiple myeloma. KEYNOTE-185 (NCT02579863) has an estimated enrollment of 640 patients, an estimated primary completion date of August 31, 2019, and an estimated study completion date of July 31, 2021, according to

“There were 19 deaths on the pembrolizumab-containing investigational arm, and nine deaths on the control arm,” according to the FDA review of KEYNOTE-185.

In addition to halting enrollment in KEYNOTE-183 and KEYNOTE-185, the FDA in July placed a partial clinical hold on KEYNOTE-023, designed to assess the Keytruda/lenalidomide/dexamethasone combination in patients who received prior anti–multiple myeloma treatment with an immunomodulatory drug (IMiD) treatment (lenalidomide, pomalidomide, or thalidomide).

KEYNOTE-023 (NCT02036502) has an estimated enrollment of 115 patients and an estimated study completion date of August 9, 2018, according to

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