update on novel combinations for relapsed/refractory disease: approved drugs
DESCRIPTION
Update on Novel Combinations for Relapsed/Refractory Disease: Approved Drugs. James R. Berenson, MD Medical & Scientific Director Institute for Myeloma & Bone Cancer Research Los Angeles, CA. Treatment Choices. Anthracyclines Doxorubicin PLD . Thal. Carfilzomib. Bortezomib. - PowerPoint PPT PresentationTRANSCRIPT
Update on Novel Combinations for Relapsed/Refractory Disease:
Approved Drugs
James R. Berenson, MDMedical & Scientific Director
Institute for Myeloma & Bone Cancer ResearchLos Angeles, CA
Treatment Choices
IMiDs Proteasome inhibitors
Chemotherapy
Steroids Clarithromycin
Clinical Trials
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Investigational Drugs
Novel Combinations
Thal
LenDex
Methylpred
Prednisone
Alkylating agents• Melphalan• Cyclophosphamide• Bendamustine
Anthracyclines• Doxorubicin• PLD
+
Bortezomib Carfilzomib
Pom
Individualize your choice for the myeloma patient based on:
Co-morbid conditions
Disease characteristics
Work/ Lifestyle
Renal,Bone,Marrow,Subjective,Rate of ProgressionGenetics?
How active is the patient?Mobility?Is potential neuropathy an issue? (e.g.- surgeon, pianist)
Diabetes mellitus (steroids)Cardiac (Doxorubicin, PLD)Neuropathy(Thalidomide)
Prior Treatments
Responseand for how long?Side effects and tolerability
Principles of Treating Relapsed/Refractory Multiple Myeloma
• Be sure a patient has really progressed before changing therapy– REPEAT MYELOMA LABS!
• Try to use drugs patient has not seen before• HOWEVER,
– progression on one drug in combination does not mean that drug will not be effective w/ another agent
• e.g., pts progressing from bortezomib w/ melphalan often respond to bortezomib w/ PLD
• Even different drugs in the same class may be active so that– bortezomib+melphalan failures may respond to other alkylating agents-
cyclophosphamide or bendamustine– LEN failures may respond to THAL and vice versa
– pts progressing from a drug at one dose may respond to the same drug at a higher dose- e.g., LEN
– the same combination may be effective again if the patient has not seen the combination in a long time
• Initial approval in multiple myeloma based on phase II data• Only single agent to demonstrate a statistically significant survival
advantage (APEX)
Study Regimen Evaluable Patients (n)
OverallResponse*
Median OS(mos)
SUMMIT Bortezomib 1.3 mg/m2 202 27% 17
CREST Bortezomib1.0 mg/m2
1.3 mg/m254
30%38%
26.7Not yet reached
APEXBortezomib
Dex1.3 mg/m2
40 mg315312
43%18%
29.823.7
Single Agent Bortezomib Relapsed/Refractory Multiple Myeloma
*EBMT criteria
P = .0272
PHA
SE II
PHA
SE II
I
Efficacy and Safety of Bendamustine plus Bortezomib in R/RMM: A Phase 1/2 trial
Patients were assigned to one of 3 cohorts receiving doses of intravenous bendamustine at 50 mg/m2 (cohort 1), 70 mg/m2 (cohort 2), or 90 (cohort 3) mg/m2 in combination with a fixed dose of intravenous bortezomib (1.0 mg/m2) according to the schedule in Figure 1.
Berenson et al., Brit J Haematol, in press
No DLT was observed at any dose level.50 mg/m2 (n = 5)70 mg/m2 (n = 4)90 mg/m2 (n = 5)
The maximum dose of bendamustine (90 mg/m2) was well tolerated in combination with bortezomib 1.0 mg/m2 and was designated as the MTD
Overall response rate Overall 48% (1 CR, 2 VGPR, 9 PR, & 7 MR)At MTD (90 mg/m2) 52%Bortezomib-exposed (n=31) 42%Alkylator-exposed (n=28) 46%
Bendamustine & Bortezomib: Results
Berenson et al., Brit J Haematol, in press
Bendamustine (B) w/ Lenalidomide (L) and Dexamethasone (D): Phase 1/2 Trial
• R/R MM patients• N=29• Regimen (28-day cycles)
– B 75-100 mg/m2 d1 & 2– L 5-10 mg qd d1-21– Dex 40 mg PO weekly
• MTD: B 75/ L 10/ D 40• Results (only 25 considered evaluable for
response)– ORR (> PR): 52% w/ 24% VGPR– MR 24%– PFS: 6.1 mo
Lentzsch et al. Blood 2012
Bortezomib + PLD vs. Bortezomib in Previously Treated MM
1° Endpoint: TTP2° Endpoints: OS*, ORR
BORT 1.3 mg/m2 PLD 30 mg/m2
N=646
RANDOMI ZE
1 4 8 11Days
(n=324)
(n=322)
q 3 weeks up to 8 cycles
q 3 weeks up to 8 cycles
*Not enough events to determine statistical significance in overall survival.ORR=overall response rate; OS=overall survival; TTP=time to progression.
Doxorubicin HCl liposome injection Prescribing Information, Rev’d May 2007
Bortezomib ± PLD MMY-3001 Trial
• Response* B (n = 322)
B+D (n = 324) P value
CR + nCR 11% 13%PR 39% 40%
ORR 41% 44% 0.43• EfficacyDOR, months 7.0 10.2 0.0008
TTP, months 6.5 9.3 0.000004
An overall survival advantage was observed for the combination arm (P=0.0476)Survival rate (15 months) 65% 76% 0.03
*By EBMT criteria
Orlowski et al. J Clin Oncol 25:3892-901 (2007)
More Frequent Dosing with PLD Improves Anti-Myeloma Effect in a SCID-hu MM Model
1Twenty days post-implantation, mice received i.p. injection of PLD once weekly. Human IgG was measured weekly in the mouse serum by ELISA.
2Seventeen days post-implantation, mice received i.p. injection of PLD once daily for three consecutive days weekly. Human IgG was measured weekly in the mouse serum by ELISA.
0 10 20 30 400
100200300400500600700800900
10001100120013001400
VehicleDoxil (0.3 mg/kg)Doxil (1 mg/kg)Doxil (3 mg/kg)
Days Post ImplantationH
uman
IgG
Lev
els
(mg/
dL)
0 10 20 30 400
100
200
300
400
500
600VehicleDoxil (0.3 mg/kg)Doxil (1 mg/kg)Doxil (3 mg/kg)Doxil (10 mg/kg)
Days Post Implantation
Hum
an I
gG L
evel
s (m
g/dL
)
Weekly Dosing1 Daily Dosing2
Campbell et al. Br J Haematol 2006
Bortezomib + PLD + Dexamethasone for Patients with Previously Untreated Myeloma:
A Phase II Trial
Days 1 2 3 4 5 6 7 8 9 10 11 29
Cycle repeatsBortezomib: 1.0 mg/m2 IV PLD: 5 mg/m2 IV infusion
Dexamethasone 40 mg IV
Berenson et al. Brit J Haematol, 2011
Response Type Number of Patients (N = 35)
Complete Response (CR)(no serum M-protein)
7 (20%)
Very Good Partial Response (VGPR)(≥ 90% decrease in serum M-protein)
3 (8.6%)
Partial Response (PR)(50-74% decrease in serum M-protein)
15 (42.9%)
Minor Response (MR)(25-49% decrease in serum M-protein)
5 (14.3%)
Objective Response (CR+VGPR+PR+MR)
30 (85.8%)
Stable Disease (SD)(no serum M-protein)
3 (8.6%)
Disease Control (CR+VGPR +PR+MR+SD)
33 (94.4%)
Progressive Disease (PD)(>25% increase in serum M-protein)
2 (5.7%)
DVD: Response Rates
Berenson et al. Brit J Haematol, 2011
Adverse Event Comparison Between DVD (Current Study) and Standard Dosing (Jakubowiak et al., Blood 2009).
Comparison of Adverse Events w/ Modified DVD vs Conventional Dosing
Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up1
Richardson PG et al. ASH 2010, abstract #304915
–Endpoints: Primary: PFS; Secondary: ORR (≥MR), DOR, TTP, OS, safety –Patients: 64 pts with relapsed/refractory MM; median age 65 years (range 32–83); ISS stage I/II/III/unknown (%): 27/25/23/25; median 2 (range 1–3) prior therapies
–Study design: – Anticoagulation with aspirin ± warfarin or LMWH, and antiviral prophylaxis against
herpes zoster were required
Richardson PG et al. ASH 2010, abstract #3049 16
–Safety: • Median cycles received:
11 (range 1–48)• Median treatment duration: 7.9
months (range 0.4–36); 66% of pts completed ≥8 cycles with all three drugs
Best response,%CR/nCR 11/14PR/VGPR 36/3ORR (≥MR) 78
• Median duration of ≥MR: 8.3 months• Median duration of ≥PR: 8.4 months
Outcomes
Median, mos
1-yr, %
2-yr, %
TTP 9.5 37 16PFS 9.5 36 15OS 26 86 55
• Results: 62 pts evaluable for response
Gr ≥3 AE, % VRD (n=64)Neutropenia 30Thrombocytopenia 22Lymphopenia 11Leukopenia 9
Hyperglycemia 9
Hyponatremia 8
Hypophosphatemia 8
Fatigue 5Diarrhea 3Limb edema 3Pain in extremity 2
Phase II Study of Bortezomib plus Lenalidomide and Dex (VRD) in Rel/Ref MM: Updated Results After >2 Years’ Follow-up
DVD-R (Bortezomib + PLD + Dexamethasone + Lenalidomide) for Patients with R/R MM:
A Phase II Trial
Days 1 2 3 4 5 6 7 8 9 10 11 12 13 14 29
Cycle repeatsBortezomib: 1.0 mg/m2 IV PLD: 4 mg/m2 IV infusion
Dexamethasone 40 mg IV
Berenson et al., Leukemia 2012
Len 10 mg po qd d1-14
DVD-R: Response RateN=39
Complete Response (CR)8* (21%)
(no serum M-protein)Very Good Partial Responses (VGPR)
4 (10%)(> 90% decrease in serum M-protein)Partial Response (PR)
7 (18%)(50-74% decrease in serum M-protein)Minor Response (MR)
14 (36%)(25-49% decrease in serum M-protein)Objective Response (CR+VGPR+PR+MR) 30 (85%)Stable Disease (SD)
4 (10%)(change in M-protein + 25%)Disease Control (CR+VGPR+PR+MR+SD) 37 (95%)Progressive Disease (PD)
2 (5%)(>25% increase in M-protein)
*Based on the modified Blade’ criteria
DVD-R Study: Adverse EventsGrade 3 adverse events included:
6 reversible neutropenia, 4 reversible anemia, 4 pneumonia, 1 dyspnea, 3 reversible thrombocytopenia, 1 reversible peripheral neuropathy, 1 mental confusion, 1 hypophosphatemia, 1 fall, 1 skin BCC, 1 allergic reaction to moxifloxacin, 1 dysphagia, 1 syncope, 1 respiratory distress.
Grade 4 adverse events included: 1 reversible thrombocytopenia & 1 anemia
No cases of stomatitis or hand-foot syndrome reported!
Treatment-emergent peripheral neuropathy (25%): Grade 1: n=8 (20%)Grade 2: n=1 (2.5%)Grade 3: n=1 (2.5%)
Retreatment w/ IMiDs for MM Patients
• Retrospective study in 140 pts treated firstline w/– THAL/DEX- 58%– LEN/DEX- 42%
• Retreatment w/ a regimen containing– THAL- 24%– LEN- 76%
• # of treatments before retreatment - median of 2 (range 1-6)
• 89% received IMiD w/ DEX• 113 considered evaluable
for response– 44% > PR– MR not reported
Madan et al. Blood 2011
LEN
LEN(n=48)
LEN
THAL (n=11)
THAL
LEN(n=58)
THAL
THAL (n=23)
> PR 54% 20% 48% 30%
PX-171-003-A0 (N=46)
PX-171-003-A1 (N=266)
Phase 2 Study Population
Dosing regimen, premedication, and hydration
were defined in 003-A0
Carfilzomib for Injection*
days 1,2,8,9,15,16(28-day cycles)
Maximum 12 cycles
Progressive disease required at study entryRelapsed from ≥2 prior lines of therapy
• Must include bortezomib• Must include thalidomide
or lenalidomideRefractory to last regimen
PX-171-003: Study Overview
Study expanded to registration trial
• Primary endpoint: Overall response rate– Assessed by an Independent Review Committee, using
International Myeloma Working Group criteria
*Cycle 1, 20 mg/m2
Cycle 2 and beyond, 27 mg/m2
Adapted from Siegel D, et al. ASCO 2011. Abstract 8027 (poster presentation).
PX-171-003-A1 (N=266): Disease characteristics
Median prior regimens (range) 5 (1-20)Median years since diagnosis (range) 5.35 (0.5-22.3)
Prior transplant 74.4%Refractory status to most recent therapyRefractory: Progression during most recent therapyRefractory: Progression within 60 days after completion of most recent therapyRefractory: ≤25% response to treatmentRelapsed: Progression after 60 days post treatment
74.4%14.3%
6.0%5.3%
Creatinine clearance <30 mL/min 2.3%Median serum b2-microglobulin (range) 4.3 (0.4-20.5)CytogeneticsNormal/FavorableUnfavorableUnknown
59.8%28.2%12.0%
PX-171-003-A1: Response
N=266Response rates*Overall response rate (ORR)Complete responseVery good partial responsePartial response
61 (22.9%)1 (0.4%)
13 (4.9%)47 (17.7%)
Median duration of response(95% CI)
7.8 months(5.6-9.2)
*As assessed by the Independent Response Review Committee
Carfilzomib in MM Patients Following 1-3 Prior Therapies
004, Phase II1:1Carfilzomib
Cohort 120 mg/m2
Relapsed / Refractory Multiple Myeloma
1-3 Prior TherapiesN = 165 Carfilzomib
Cohort 220 mg/m2→27 mg/m2
Bortezomib-treated
Bortezomib-naïve
Bortezomib-naïve
Bortezomib-naïve Bortezomib-treatedN 129 36Median age 65 years 63 yearsMedian # prior therapies
2 3
Carfilzomib: IV, days 1, 2, 8, 9, 15, and 16 every 28 days for up to 12 cycles
Stewart AK, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8026. Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813.
Carfilzomib Monotherapy MM Patients With 1-3 Prior Therapies
Bortezomib-Treated Cohort 1 (20 mg/m2 Carfilzomib)n = 34
ORR 21%CBR (> MR) 33%Median TTP 8.1 monthsMedian DOR (> PR) 11.5 months
Stewart K, et al. Hematologica. 2010;95(S2). Abstract 1099. Vij R, et al. ASH Annual Meeting Abstracts. 2011;118(21):813.
Bortezomib-naïve Cohort 1 (20 mg/m2)n = 59
Cohort 2 (20→27 mg/m2)n = 70
ORR 42% 52%CBR 59% 64%CR 3% 2%VGPR 14% 27%Median TTP 8.3 mo Not reachedMedian DOR 13.1 mo Not reachedMedian PFS 8.2 mo Not reached
Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed / Refractory MM
CarfilzomibLenalidomideLow-dose dex
MM: 1-3 Prior Therapies
N = 52
1o EndpointORR
2o EndpointDOR, TTP, OS, PFS, Safety
Wang M, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8025.
CRdN = 51
Median age 63 yearsMedian # of prior therapies Prior bortezomib Prior lenalidomide Prior lenalidomide and bortezomib Prior thalidomide
285%73%50%44%
Carfilzomib / Lenalidomide / Dex (CRd) in Relapsed/Refractory MM
Grade 3/4 Adverse Events CRdN = 51
Neutropenia 23%Thrombocytopenia 15%Anemia 15%Hypophosphatemia 13%Fatigue 12%
Response CRdN = 51
ORR 78% CR / nCR 24% VGPR 18% PR 37%
Wang M, et al. ASCO Meeting Abstracts. 2011;29(15 suppl):8025.
ORR, overall response rate; CR, complete response; nCR, near complete response; VGPR, very good partial response; PR, partial response.
• Nontraditional intrapatient Phase I/II trial • Eligibility: Progressive disease while on
bortezomib or relapsed within 12 wks of the last dose of bortezomib in a combination regimen
• Carfilzomib replaces bortezomib in combination with:– Alkylating agent– Anthracycline– Glucocorticosteroid– IMiD
A Phase I/II Study of Carfilzomib as a Replacement for Bortezomib for Multiple Myeloma Patients Failing
Bortezomib-Containing Regimens
Study Design (cont’d)• Study treatment
– Carfilzomib• starting at 20 mg/m2 for the 1st cycle• increased to 27, 36 and 45 mg/m2 during cycles 2, 3 and
4, respectively if no DLT is observed– DLT considered > Grade 2
• administered on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle
– Cycle length, schedule(s) and dose(s) of other drugs identical to that of the previous bortezomib-containing regimen
• A patient must complete a minimum of a full cycle without DLT before continuing onto a subsequent cycle (cycles 1-4 only)
• Maximum # of cycles- 8
ResultsDemographicsEnrolled (N) 32Efficacy (N) 24Age (median) 67Sex (M:F) 21:11Prior RegimensNumber of prior regimens- median (range) 6 (1-18)Number of prior bortezomib-containing regimens- median (range) 2 (1-13)
Regimen Details
Cycle length
8 pts- 21-day 24 pts- 28-day
Cycles completed, median (range)
3 (range 0-12)
Follow-up median(range)
5.9 mo(0.4-14.4 mo)
Number of DLTs
8 (25%)
Regimen in addition to carfilzomib (N=32)Dexamethasone 9 (28%)Cyclophosphamide+ ascorbic acid 5 (16%)Cyclophosphamide+ascorbic acid+dexamethasone
1 (3%)
Melphalan 1 (3%)Bendamustine 3 (9%)Bendamustine+methylprednisolone 1 (3%)PLD 1 (3%)PLD+dexamethasone 5 (16%)Lenalidomide 2 (6%)Lenalidomide + dexamethasone 1 (3%)Lenalidomide + dexamethasone + PLD 1 (3%Thalidomide + dexamethasone 1 (3%)Thalidomide + lenalidomide + bendamustine + clarithromycin + methylprednisolone
1 (3%)
Best Response # of Patients %
PD 2 8%SD 4 17%MR 5 21%PR 7 29%VGPR 4 17%CR 2 8%Overall Response Rate (PR+VGPR+CR)
13 54%
Clinical Benefit Rate (MR+PR+VGPR+CR) 18 75%
Efficacy (N=24)
Summary• Intrapatient Phase I/II trial of MM patients
refractory to bortezomib combination therapy with and without IMiDs
• Treatment with same regimen w/ carfilzomib (CAR) replacing bortezomib
• CAR escalated from 20 to 27, 36, and 45 mg/m2 during cycles 1-4; maximum of 8 cycles
• MTD for one regimen (CY+CAR) reached at the maximum dose of CAR (45 mg/m2) with no DLT
• Well tolerated• Clinical benefit rate 75% including 8% CR, 17%
VGPR, 29% PR, & 21% MR– Responses observed with all drugs!
• Phase I/II, open-label, multi-center trial investigating weekly carfilzomib + dexamethasone in R/R MM patients
• Phase I: – 28-day cycle– Carfilzomib 45, 56 or 70 mg/m2 on days 1, 8 & 15– Dexamethasone IV at 40 mg days 1, 8, 15, & 22
• Phase II:– Carfilzomib at MTD on days 1, 8 & 15– Dexamethasone IV at 40 mg days 1, 8, 15, & 22
• Enrollment: second cohort (56 mg/m2) currently being treated!
A Phase I/II Trial of Weekly Carfilzomib in Combination With IV Dexamethasone for R/R
Multiple Myeloma
HDAC Inhibitor Vorinostat & Bortezomib for R/R MM: VANTAGE 088: Phase III Trial
Bortezomib + Placebo
Bortezomib + VorinostatMultiple Myeloma
1-3 Prior TherapiesN = 637
R
Bortezomib + Vorinostat
Bortezomib + Placebo
P
ORR 56% 41% < 0.0001CBR 71% 54% < 0.0001Median PFS 7.63 mo 6.83 mo < 0.01Median OS NR 28.1 mo 0.35
Dimopoulos MA, et al. ASH Annual Meeting Abstracts. 2011;118(21):811.
ORR, overall response rate; CBR, clinical benefit rate; PFS, progression-free survival; OS, overall survival.
Vorinostat, Lenalidomide & Dexamethasone for R/R MM
1:1Vorinostat (300 or 400 mg, 1x daily)Lenalidomide (10, 20, 25 mg daily)Dexamethasone (40 mg weekly)
Relapsed / Refractory MMN = 28
ResponseVorinostat / Lenalidomide /
DexamethasoneN = 28
ORR 46% CR 7% > SD 86%
Siegel D, et al. Blood. 2009;114(22). Abstract 305. Vorhees PM, et al. Blood. 2009;114(22). Abstract 306.
Serious AE• Neutropenia, diarrhea, ↑ QTc, extrasystole, dehydration, ↑ troponin, fever
Grade 3 DVT in 2 patients No treatment-related deaths
Novel Combinations of Approved Drugs Greatly Expand the Therapeutic Options
for R/R Myeloma Patients!• Approved drugs
– Novel combinations– Modifications of dose and schedule
• Improve efficacy• Better tolerability
• Many new drugs in development– Similar targets
• Proteasome inhibitors- carfilzomib (FDA-approved!)• IMiDs- pomalidomide
– New classes of agents• HDAC inhibitors- vorinostat, panobinostat• Monoclonal antibodies
– Anti-CS-1- elotuzumab– Anti-CD40- dacetuzumab
• MTOR inhibitors- temsirolimus• PI3K inhibitors- perifosine