James R. Berenson1, 2, 3, Ori Yellin1, Robert Dichmann4, Dipti Patel- Donnelly5, Ralph V. Boccia6, James D. Hilger1, Youram Nassir7, Regina A. Swift2 and Robert Vescio8

1Oncotherapeutics, Los Angeles, CA, 2James R. Berenson, MD, Inc., Los Angeles, CA, 3Institute for Myeloma and Bone Cancer Research, Los Angeles, CA, 4Central Coast Medical Oncology, Santa Maria, CA, 5Fairfax Northern Virginia Hematology Oncology, Fairfax, VA, 6Center for Cancer and Blood Disorders, Bethesda, MD, 7Cancer Care Institute, Los Angeles, CA, 8Cedars-Sinai Medical Center, Los Angeles, CA

Background

Recent data has shown that single-agent CFZ can produce responses among MM pts refractory to previous treatment regimens including those containing BTZ. We conducted an intrapatient Phase 1/2 trial investigating the safety and efficacy of CFZ as a replacement for BTZ in BTZ‑containing regimens to which pts have progressed.

Methods

Eligible pts had to have progressed while receiving their most recent BTZ‑containing regimen after at least 4 doses of BTZ at > 1.0 mg/m² in < 4 weeks per cycle. Combination regimens containing an alkylating agent, anthracycline, or a glucocorticosteroid were eligible. CFZ replaced BTZ in each regimen via intravenous administration over 30 min on days 1, 2, 8, 9, 15, and 16 of each cycle. Treatment continued using the same dose(s) and schedule(s) of each drug administered in the BTZ‑containing regimen. CFZ doses were escalated on each of the first 4 cycles from 20 to 27, 36, and 45 mg/m² or until a maximum tolerated dose (MTD) was reached for that regimen.

Results

Of 19 enrolled pts 13 are evaluable to date and 6 have recently started treatment. Pts received a median of 7 (range, 1-18) prior treatments and 5 (range, 1-5) different BTZ-containing regimens.  Pts were treated with CFZ and the following different combinations: bendamustine (BEND) alone, BEND + methylprednisolone, dexamethasone (DEX) alone, DEX + pegylated liposomal doxorubicin, ascorbic acid + cyclophosphamide, and melphalan alone.

Pts have completed a median of 3 cycles. Clinical benefit was seen in 10 (77%) pts (complete response = 8%; very good partial response = 8%; partial response = 31%; minor response = 31%) with another 23% showing stable disease. The median time to progression (range: 2-8 months) has not been reached and only 2 pts have progressed. The most common grade 3/4 adverse events were thrombocytopenia occurring in 5 pts (all = grade 3 except 1 event) and fever occurring in two pts (grade 3). Four pts experienced a serious adverse event but no regimen has reached a MTD.

Conclusions

These early results suggest that CFZ is an effective and tolerable replacement for BTZ for pts who are refractory to BTZ-containing combination regimens.

For more information on these trials, please visit www.clinicaltrials.gov.