1. Phase Ib PAVO Study: Subcutaneous Daratumumab in Relapsed/Refractory Multiple Myeloma
New Findings in Hematology: Independent Conference Coverage of ASH 2016*; December 3-6, 2016; San Diego, California
*CCO is an independent medical education company that provides state-of-the-art medical information to healthcare professionals through conference coverage and other educational programs.
This activity is supported by educational grants from Amgen, Celgene Corporation, Incyte, Merck, and Seattle Genetics.

2. PAVO: Background
Daratumumab, recently approved anti-CD38 IgG1k monoclonal antibody, effective MM treatment in combination with Rd or Vd in the second-line setting and beyond or as single agent in MM after ≥ 3 lines of therapy[1-3]
Currently administered IV
Most IV-associated infusion-related reactions with daratumumab occur during first infusion but are grade 1/2[2]
Current phase Ib trial sought to determine safety, pharmacokinetics, and efficacy of SC daratumumab + recombinant human hyaluronidase enzyme (rHuPH20) in pts with relapsed/refractory MM[4]
rHuPH20 allows for more rapid absorption of SC injected agents
MM, multiple myeloma; RD, lenalidomide/dexamethasone; Vd, bortezomib/dexamethasone.
1. Dimopoulos MA, et al. N Engl J Med. 2016;375: Palumbo A, et al. N Engl J Med. 2016;375: Lonial S, et al. Lancet. 2016;387: Usmani SZ, et al. ASH Abstract 1149.
Slide credit: clinicaloptions.com

3. PAVO: Study Design
Open-label, multicenter, dose-finding, proof-of-concept phase Ib study
Next stage of study will randomize pts to recommended SC dose vs daratumumab IV 16 mg/kg
Recommended SC dose will be derived from pharmacokinetic and safety results from above design
Primary endpoints: Ctrough of daratumumab at cycle 3/Day 1 and safety
Secondary endpoints: ORR, CR, DoR, time to response
4-wk treatment cycles
Every wk for 8 wks
Every 2 wks for 16 wks
Every 4 wks thereafter
Infusion time
1200 mg: 20 min (60 mL)
1800 mg: 30 min (90 mL)
Daratumumab 1200 mg SC + rHuPH20 30,000 U SC
(n = 8)*
Pts with measurable R/R MM, ≥ 2 lines of therapy, no prior anti-CD38 therapy
(N = 53)
Daratumumab 1800 mg SC + rHuPH20 45,000 U SC
(n = 45)*
*Pre/postinfusion medication includes acetaminophen, diphenhydramine, montelukast, and methylprednisolone.
DoR, duration of response; MM, multiple myeloma; R/R, relapsed/refractory.
Slide credit: clinicaloptions.com
Usmani SZ, et al. ASH Abstract 1149.

4. PAVO: Baseline Demographics
Characteristic
1200 mg (n = 8)
1800 mg (n = 45)
Median age, yrs (range)
≥ 75 yrs, %
66 (49-78) 13
63 (36-79) 9
Median weight, kg (range)
75.0 ( )
74.8 ( )
Baseline ECOG PS, % 1 2 25 63 24 73
ISS stage, % I II
III 17 50 33 47 20
Median time from diagnosis,
yrs (range)
6.55 ( )
5.94 ( )
Characteristic
1200 mg (n = 8)
1800 mg (n = 45)
Prior lines of therapy, median (range)
≤ 3 lines, %
> 3 lines, %
5 (2-10) 33 63
4 (2-11) 36 64
Prior ASCT, % 82
Prior PI, %
Prior bortezomib
100 96
Prior IMiD, %
Prior lenalidomide
Refractory, %
PI only
IMiD only
Both PI and IMiD
Last line of therapy 13 88 4 20 58 71
ASCT, autologous stem cell transplantation; ECOG, Eastern Cooperative Oncology Group; IMiD, immunomodulatory drug; ISS, International Staging System; PI, proteasome inhibitor; PS, performance status.
Slide credit: clinicaloptions.com
Usmani SZ, et al. ASH Abstract 1149.

5. PAVO: Pt Disposition Median follow-up Median duration of treatment
1200 mg: 6.4 mos (range: )
1800 mg: 4.3 mos (range: )
Median duration of treatment
1200 mg: 2.6 mos (range: )
1800 mg: 3.4 mos (range: )
1200 mg (n = 8)
1800 mg (n = 45)
Patients who discontinued treatment, % 88 33
Progressive disease 63 27
Withdrawal by consent 13
Physician decision 4
Death 2
Slide credit: clinicaloptions.com
Usmani SZ, et al. ASH Abstract 1149.

6. PAVO: Treatment-Related AEs
AE profile with SC daratumumab consistent with IV daratumumab
Treatment-Related AEs, %
1200 mg (n = 8)
1800 mg (n = 45)
Drug-related 63 62
Serious drug-related 13 7
Grade ≥ 3 40
All-grade hematologic > 25%
Anemia
Thrombocytopenia 25 38 31 18
All-grade nonhematologic > 25%
Upper respiratory tract infection
Insomnia
Decreased appetite 9
Grade 3/4 Treatment-Related AEs, %
1200 mg (n = 8)
1800 mg (n = 45)
Anemia 13
Thrombocytopenia 7
Neutropenia
Lymphopenia
Hypertension 25 4
Fatigue 2
Device-related infection
Hyponatremia
AE, adverse event.
Slide credit: clinicaloptions.com
Usmani SZ, et al. ASH Abstract 1149.

7. PAVO: Infusion-Related Reactions
1200 mg (n = 8)
1800 mg (n = 45)
Overall 13 24
Chills 9
Pyrexia
Pruritus 4
Dyspnea
Flushing 2
Hypertension
Hypotension
Nausea
Infusion-Related Reaction, n (%)
1200 mg (n = 8)
1800 mg (n = 45)
Noncardiac chest pain 13
Oropharyngeal pain 2
Paresthesia
Rash
Sinus headache
Tongue edema
Vomiting
Wheezing
IRR, infusion-related reaction.
No grade 4 IRRs in either dosing group; 1 grade 3 IRR (dyspnea) in 1200-mg group
All IRRs occurred during first infusion and within first 4 hrs
Slide credit: clinicaloptions.com
Usmani SZ, et al. ASH Abstract 1149.

8. PAVO: Efficacy
PK for 1800-mg SC dose similar to that of 16-mg/kg IV dose
Mean concentration-time outcomes for daratumumab mg SC
Cmax similar to 16 mg/kg IV dose
Cmax lower during initial weekly administration
Ctrough higher than with 1200-mg SC dose
Response, %
1200 mg (n = 8)
1,00 mg (n = 45)
ORR 25 38
sCR 2 CR
VGPR 7 PR 29 MR 13 11 SD 50 PD 12
MR, minimal response; PD, progressive disease; PK, pharmacokinetic; sCR, stringent CR, VGPR, very good PR.
Slide credit: clinicaloptions.com
Usmani SZ, et al. ASH Abstract 1149.

9. PAVO: Conclusions
SC administration of daratumumab + rHuPH20 safe and effective
Both dose groups showed responses to SC daratumumab
1800-mg group had deeper responses vs 1200-mg group
Preliminary efficacy similar to IV daratumumab: 38% ORR, including 1 sCR
AEs for SC daratumumab + rHuPH20 similar to IV daratumumab with no new safety signals
Low IRR incidence and intensity with SC daratumumab
PK of SC daratumumab 1800 mg similar to 16 mg/kg IV administration
AE, adverse event; IRR, infusion-related reaction; PK, pharmacokinetic; sCR, stringent CR.
Slide credit: clinicaloptions.com
Usmani SZ, et al. ASH Abstract 1149.

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