While daratumumab was approved by the U.S. Food and Drug Administration (FDA) as an intravenous (IV) infusion for the treatment of multiple myeloma (MM), the infusion can take several hours, potentially affecting patient quality of life and adding costs to the therapy. According to results from the open-label, multicenter, dose-escalation phase Ib PAVO study, subcutaneous administration of the anti-CD38 monoclonal antibody was safe and effective, and has the advantage of taking only minutes to deliver.
The PAVO trial, conducted by Saad Z. Usmani, MD, from the Department of Hematologic Oncology and Blood Disorders at the Levine Cancer Institute/Carolinas HealthCare System in Charlotte, North Carolina, and authors, assessed the safety, pharmacokinetics, and efficacy of subcutaneous daratumumab administration in patients with relapsed or refractory MM.
All patients had received ≥2 prior lines of therapy (including a proteasome inhibitor [PI] and an immunomodulatory drug [IMiD]). To facilitate systemic absorption of the drug into the abdominal wall, daratumumab was co-administered with recombinant human hyaluronidase enzyme (rHuPH20).
As of November 15, 2016, 41 patients had been treated with subcutaneous daratumumab at one of two doses: daratumumab 1,200 mg (in 60 mL doses over 20 minutes; n=8) or daratumumab 1,800 mg (in 90 mL doses over 30 minutes; n=33).
Dr. Usmani noted that the baseline patient demographics were “well balanced between the treatment groups, [and] this patient population was fairly comparable with the daratumumab monotherapy studies that have been reported and published in the past.”
In the 1,200 mg cohort (median age = 66 years; range = 49-78 years), patients had received a median of five prior lines of therapy (range = 2-10 therapies), and 63 percent had undergone prior hematopoietic cell transplantation (HCT). Most were double-refractory to PIs and IMiDs (63%), 13 percent were IMiD-refractory only, and no patients were PI-refractory only. In the 1,800 mg cohort (median age = 63 years; range = 44-75), patients had received a median of four prior lines of therapy (range = 2-7 therapies), and most had undergone prior HCT (76%). Most patients (65%) were refractory to both PIs and IMiDs, while 12 percent were refractory to IMiDs only, and 6 percent were refractory to PIs only.
Daratumumab plus rHuPH20 was administered via a syringe pump at rotating sites on the abdomen in the following four-week treatment cycles:
- once weekly for 8 weeks
- every 2 weeks for 16 weeks
- every 4 weeks thereafter
Pre- and/or post-infusion medications included paracetamol, diphenhydramine, montelukast, and methylprednisolone.
After a median follow-up of 6.4 months (range = 1.6-12 months) in the 1,200 mg cohort and 4.3 months (range = 0.8-8.6 months) in the 1,800 mg cohort, and median treatment durations of 2.6 months (range = 0.7-12 months) and 3.4 months (range = 0.7-8.6 months), respectively, Dr. Usmani reported that “the tolerability, safety, and pharmacokinetic data support continued development of subcutaneous daratumumab in different settings.”
Median time to response was 14 weeks (range = 8-20 weeks) in the 1,200 mg arm and 4 weeks (range = 4-8 weeks) in the 1,800 mg arm. Response rates were higher and deeper in the higher-dose group: Overall response rate (ORR) was 38 percent in the 1,800 mg cohort, including a stringent complete response rate of 2 percent, a very good partial response (PR) of 7 percent, and a PR rate of 29 percent; the ORR in the 1,200 mg cohort was 25 percent, all of which were PRs.
The response rates in both groups were consistent with what has been observed with the IV formulation, the authors reported.
Subcutaneous administration also appeared to be well tolerated, with infusion-related reactions (IRRs) reported in 22 percent of patients (n=9/41), most of which were grades 1/2 in severity, including chills, fever, rigors, vomiting, itching, edema of the tongue, non-cardiac chest pain, and wheezing. One patient developed grade 3 dyspnea and another patient required hospitalization due to fever and chills after the first infusion (both grade 2). All IRRs developed during or within six hours of the first subcutaneous infusion and were controlled with antihistamine, corticosteroid, antiemetic, or bronchodilator treatment. IRRs were not reported in subsequent infusions.
The most common all-grade non-hematologic treatment-related adverse events (AEs) were upper respiratory infection (38% and 9% in the 1,200 mg and 1,800 mg cohorts, respectively), insomnia (38% and 9%), and decreased appetite (38% and 7%). Grade ≥3 treatment-related AEs were reported in 12 percent of patients (n=5/41), including two cases of fatigue and one case each of influenza, hypertension, dyspnea, and tumor lysis syndrome.
The most common all-grade hematologic treatment-related AEs were anemia (25% and 31% in the 1,200 mg and 1,800 mg cohorts, respectively) and thrombocytopenia (38% and 18%).
“The AE profile appeared to be consistent with what we have observed with the IV daratumumab formulation,” Dr. Usmani said.
In addition, pharmacokinetic analysis revealed that patients receiving the subcutaneous 1,800 mg dose achieved serum trough concentrations similar to or greater than the daratumumab 16 mg/kg IV formulation. Patients in the 1,200 mg dose arm showed lower levels of serum trough concentration, and, based on these results, the recommended dose for the second phase of the PAVO study is subcutaneous daratumumab 1,800 mg.
“Subcutaneous daratumumab administration appears safe, effective, and convenient for patients in an approximately 30-minute infusion time for the 1,800 mg fixed dose,” Dr. Usmani told ASH Clinical News. “There was a lower incidence of IRRs and comparable ORR in the PAVO study, compared with previously published experience with intravenous daratumumab, [including the] GEN501 and SIRIUS trials.”
However, Dr. Usmani noted that head-to-head comparative data do not exist between the two formulations, so the results from this trial will need to be demonstrated in randomized clinical trials.
In part two of the phase I PAVO study, patients will be randomized 1:1 to receive the recommended dose of daratumumab or intravenous daratumumab 16 mg/kg.
Usmani SZ, Nahi H, Mateos MV, et al. Open-label, multicenter, dose escalation phase 1b study to assess the subcutaneous delivery of daratumumab in patients (pts) with relapsed or refractory multiple myeloma (PAVO). Abstract #1149. Presented at the 2016 ASH Annual Meeting, December 5, 2016; San Diego, CA.