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838 Subcutaneous Delivery of Daratumumab in Patients (pts) with Relapsed or Refractory Multiple Myeloma (RRMM): Pavo, an Open-Label, Multicenter, Dose Escalation Phase 1b Study

Program: Oral and Poster Abstracts
Type: Oral
Session: 653. Myeloma: Therapy, excluding Transplantation: Studies in Relapsed and Refractory Multiple Myeloma
Monday, December 11, 2017: 5:15 PM
Bldg C, Lvl 1, Hall C1 (Georgia World Congress Center)

Ajai Chari1*, Hareth Nahi2*, Maria-Victoria Mateos3, Henk M. Lokhorst4*, Jonathan L. Kaufman, MD5, Philippe Moreau6*, Albert Oriol, MD7*, Torben Plesner, MD8, Lotfi Benboubker, MD9*, Peter Hellemans10*, Tara Masterson11*, Pamela L Clemens11*, Kevin Liu12*, Jesus F. San-Miguel, MD13 and Saad Z Usmani, MD14

1Tisch Cancer Institute, Mount Sinai School of Medicine, New York, NY
2Karolinska Institute, Department of Medicine, Division of Hematology, Karolinska University Hospital at Huddinge, Stockholm, Sweden
3University Hospital of Salamanca/IBSAL, Salamanca, Spain
4Department of Hematology, VU University Medical Center, Amsterdam, Netherlands
5Winship Cancer Institute, Emory University, Atlanta, GA
6University Hospital of Nantes, Nantes, France
7Institut Català d’Oncologia, HGTiP, Barcelona, Spain
8Vejle Hospital and University of Southern Denmark, Vejle, Denmark
9Service d’Hématologie et Thérapie Cellulaire, Hôpital Bretonneau, Centre Hospitalier Régional Universitaire (CHRU), Tours, France
10Janssen Research & Development, Beerse, Belgium
11Janssen Research & Development, LLC, Spring House, PA
12Janssen Research & Development, LLC, Raritan, NJ
13Clínica Universidad de Navarra-CIMA, IDISNA, CIBERONC, Pamplona, Spain
14Levine Cancer Institute/Carolinas HealthCare System, Charlotte, NC

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; Amgen: 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; Celgene: 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: Novartis: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene, Janssen, Takeda, Novartis, Amgen, Roche: Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceutical: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Millennium: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: 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.

*signifies non-member of ASH