Subcutaneous Delivery of Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma (RRMM): Pavo, an Open-Label, Multicenter, Dose Escalation Phase 1b Study
Authors: Chari Ajai , Nahi Hareth , Mateos Maria-Victoria , Lokhorst Henk M. , Kaufman Jonathan L. , Moreau Philippe , Oriol Albert , Plesner Torben , Benboubker Lotfi , Hellemans Peter , Masterson Tara , Clemens Pamela L , Liu Kevin , San-Miguel Jesus F. , Usmani Saad Z 
Published: April 2021

Abstract
Introduction : Daratumumab (DARA), a CD38-targeted human monoclonal antibody, is approved as monotherapy and in combination with bortezomib (proteasome inhibitor; PI) or immunomodulatory drugs (IMiD; lenalidomide or pomalidomide) in pts with RRMM. DARA is administered intravenously (IV) and is associated with infusion related reactions (IRRs) in 46% of pts. We previously reported data from PAVO (NCT02519452), an open-label, multicenter, phase 1b study in RRMM, showing that subcutaneous (SC) delivery of DARA with recombinant human hyaluronidase enzyme (rHuPH20) by SC infusion of a mix and deliver formulation (DARA-MD) was well tolerated with low rates of IRRs (Usmani SZ, et al. ASH 2016; abstract 1149). DARA + rHuPH20 also demonstrated an efficacy profile consistent with IV DARA. We present updated data, including initial safety and efficacy findings from an additional cohort that received DARA co-formulated with rHuPH20 (DARA SC), which was delivered by manual SC injection.
Methods : RRMM pts had an Eastern Cooperative Oncology Group performance status ≤2 and received ≥2 prior lines of therapy including a PI and an IMiD. To determine the recommended SC dose for Part 2 of this 2-part study, DARA-MD was administered via SC infusion through a syringe pump from 20 to 30 min in Part 1. Pts were administered DARA 1200 mg + rHuPH20 30000 U (in 60 mL) or DARA 1800 mg + rHuPH20 45000 U (in 90 mL) in 28-day cycles: weekly in Cycles 1-2, every 2 weeks in Cycles 3-6, and every 4 weeks thereafter. The 1,800 mg dose level was selected for Part 2.
In Part 2, a concentrated co-formulation of the selected DARA SC (1800 mg in 15 mL) and rHuPH20 (30000 U) dose in a single, pre-mixed vial was administered in 3 to 5 minutes by manual SC injection. In both parts, the primary endpoints were Ctrough of DARA up to Cycle 3 Day 1 and safety. Secondary endpoints included overall response rate (ORR), rate of complete response (CR), and time to response.
Results : At the clinical cut-off of June 30, 2017, 53 pts were enrolled in Part 1 (DARA-MD 1200 mg, n=8; DARA-MD 1800 mg, n=45) and 25 pts were enrolled in Part 2 (DARA SC 1800 mg). 0/8 (0%), 12/45 (27%), and 25/25 (100%) pts receiving DARA-MD 1200 mg, DARA-MD 1800 mg, and DARA SC 1800 mg, respectively, remain on treatment; the median duration of treatment was 2.6 (0.7-12.0), 5.4 (0.7-16.6+), and 1.4 (0.5-2.3+) months, respectively.
In Part 1, 100% and 73% of pts discontinued treatment in the DARA-MD 1200 mg and DARA-MD 1800 mg dose cohorts, respectively, due to progressive disease (75% and 58%), physician decision (0% and 9%), death (13% and 2%), withdrawal by pt (13% and 2%), and other (0% and 2%); in Part 2 with shorter follow up, none discontinued treatment. One pt receiving DARA-MD 1200 mg died due to adverse event (aspiration pneumonia) and 2 pts receiving DARA-MD 1800 mg died due to disease progression; no deaths occurred in the DARA SC 1800 mg cohort.
IRRs were reported in 13%, 24% and 4% pts receiving DARA-MD 1200 mg, DARA-MD 1800 mg, and DARA SC 1800 mg, respectively. One grade 3 IRR of dyspnea occurred in the DARA-MD 1200 mg cohort; no grade 3/4 IRRs occurred in pts receiving DARA-MD 1800 mg or DARA SC 1800 mg. SC administration was well tolerated in the DARA-MD 1200 mg, DARA-MD 1800 mg, and DARA SC 1800 mg cohorts, with 63%, 29%, and 20% of pts experiencing reversible erythema and 50%, 22%, and 0% of pts experiencing reversible induration at the infusion/injection site, respectively.
Among DARA-MD 1200 mg, DARA-MD 1800 mg, and DARA SC 1800 mg cohorts, treatment-emergent adverse events (TEAEs) occurred in 100%, 98% and 84% pts, respectively; 63%, 49% and 32% were grade 3 or 4 (Table). Serious TEAEs occurred in 50%, 31%, and 4% pts. No pts discontinued treatment due to TEAEs.
As of August 1, 2017, in the DARA-MD 1800 mg cohort, ORR was 42%, and the rates of ≥VGPR and ≥CR were 20% and 7%, respectively. In the DARA SC 1800 mg cohort, a preliminary ORR of 42% was observed which requires confirmation at follow up.
Updated safety, efficacy and pharmacokinetic data will be presented at the meeting.
Conclusions : SC administration of DARA + rHuPH20 was well tolerated, with lower than expected rates of IRRs in all groups, but particularly in those treated with DARA SC 1800 mg administered over only 3-5 minutes. Planned phase 3 studies will use DARA SC at the dose identified in Part 2.

Disclosures
Chari: Acetylon Pharmaceuticals: Other: Research funding (to AC's institution); Millennium: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Consultancy, Other: Research funding (to AC's institution); travel; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Onyx: Research Funding; Pharmacyclics: Research Funding; Biotest: Other: Research funding (to AC's institution); Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travel, Research Funding. Mateos: Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Lokhorst: Amgen: Membership on an entity's Board of Directors or advisory committees; Janssen, Genmab: Membership on an entity's Board of Directors or advisory committees, Research Funding. Kaufman: Amgen, Novartis: Research Funding; Amgen, Roche, BMS, Seattle Genetics, Sutro Biopharma, Pharmacyclics: Consultancy. Moreau: Takeda: Honoraria; Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Novartis: Consultancy, Honoraria; Onyx Pharmaceutical: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Oriol: Celgene: Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: sponsored symposia, Speakers Bureau. Plesner: Janssen: Research Funding; Janssen, Takeda: Consultancy; Janssen, Genmab: Membership on an entity's Board of Directors or advisory committees. Benboubker: Takeda, Celgene, Janssen, Amgen: Consultancy. Hellemans: Janssen: Employment. Masterson: Janssen: Employment. Clemens: Janssen: Employment. Liu: Janssen: Employment. San-Miguel: Takeda, Celgene, Novartis, Amgen, Janssen, Bristol-Myers Squibb: Consultancy. Usmani: Skyline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Onyx: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Array BioPharma: Honoraria, Research Funding; Pharmacyclics: Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Speakers Bureau.