Primary: To characterize the safety and tolerability of PDR001 and/or MBG453 in combination with decitabine or azacitidine in relapsed/refractory AML patients, de novo AML patients not candidates for standard induction therapy, or high risk or…
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Adverse events. Dose Limiting Toxicities (DLTs).
Secondary outcome
ORR (Objective response rate), BOR (Best overall response), PFS (Progression
free survival), TTP (Time to progression), DOR (Duration of response). PK
parameters. Anti-PDR001 and anti-MBG453 antibodies.
Background summary
The prognosis for patients with de novo AML who cannot tolerate standard
therapy and those with relapsed or refractory (R/R) AML and high risk MDS
remains extremely poor, and despite the significant unmet medical need, few
effective treatment options exist. There is strong evidence and promise for
checkpoint inhibition; however, it will be important to determine the ideal
checkpoint inhibitor strategy and to consider combination therapies in order to
optimize anti-tumor immunity.
Expanding the responses to immunomodulatory therapy is an important focus of
current oncology research. Combination therapies using multiple inhibitors of
immune function could significantly improve response rates, and efforts to
target different steps in the anti-tumor immune response hold the promise of
achieving sustained anti-tumor immunity.
The purpose of this study is to combine the standard of care hypomethylating
agent decitabine with inhibitors of either PD-1 or TIM-3, or both in order to
identify an optimized checkpoint inhibitor strategy in AML and MDS. Decitabine
will be used both for its anti-tumor activity as well as its potential as an
immunomodulatory agent allowing for the implementation of focused checkpoint
inhibition. Additionaly also MBG453 with or without PDR001
No specific molecular selection will be applied as the data available at
present generally do not support excluding patients based on approved molecular
diagnostic tests such as PDL1 expression.
Study objective
Primary:
To characterize the safety and tolerability of PDR001 and/or MBG453 in
combination with decitabine or azacitidine in relapsed/refractory AML patients,
de novo AML patients not candidates for standard induction therapy, or high
risk or intermediate risk MDS patients, and to identify recommended doses for
future studies.
Secondary:
Preliminary antitumor activity. Pharmacokinetics (PK). Immunogenicity.
See also protocol.
Study design
Multicenter phase Ib open-label multi-arm study.
6 treatment arms:
1. Fixed dose of decitabine in combination with fixed dose PDR001 (Arm 1)
2. Fixed dose of decitabine in combination with escalating dose MBG453 (Arm 2)
3. Fixed dose of decitabine in combination with fixed dose PDR001 and
escalating dose MBG453 (Arm 3)
4. Fixed dose of MBG453 , to be confirmed during the course of the trial
(Arm 4)
5. fixed dose of PDR001 and Fixed dose of MBG453 , to be confirmed during
the course of the trial (Arm 4)
6. Fixed dose of azacitidine in combination with escalating dose MBG453 (Arm
6)
The assignment of a patient to a particular arm or dose level will be
coordinated by Novartis and will be based on the dose levels available at the
time the patient consents to participation in the study.
Treatment until complete response during treatment or until progression or
unacceptable toxicity.
If applicable: follow-up for progression. Follow-up for safety 5 months.
Follow-up for survival.
207 subjects.
See also protocol.
Intervention
Treatment with decitabine in combination with PDR001 and/or MBG453. Treatment
with MBG453 with or without PDR001. Treatment with azacitidine in combination
with MBG453.
Study burden and risks
Risk: Adverse effects of decitabine in combination with PDR001 and/or MBG453 or
azacitidine in combination with MBG453.
Burden: 6-7 cycles of 4 weeks (combination therapy) and 3 optional cycles of
decitabine monotherapy. Visits on day 1, 8, 15 and 22 of the first and third
cycle and day 1 of every other cycle. Visit duration mostly 1-4 hours.
IV infusions of PDR001 on day 8, MBG453 day 8 and 22, decitabine on the 1st 5
days of every cycle and azacitidine on the first 7 days of every cycle.
Infusions of 250 mL.
Physical examination: day 1 of every cycle and day 8 of cycles 1 and 3,
screening, end of treatment.
Blood tests (10-40 mL/occasion): day 1 of every cycle and day 8 of cycles 1 and
3, screening, end of treatment and follow-up for progression. Multiple PK
sampling (2-4 times) day 1 and 8 of cycles 1 and 3.
ECG: day 1 and 8 of cycles 1 and 3, screening, end of trial.
CT-/MRI scan: screening, will be repeated if needed.
Bone marrow aspirate and/or 4 times and during follow-up for progression (1st
may be replaced by recent archival material).
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
1. Male or female patients * 18 years of age with
ARM 1-2-3 :
* Refractory/relapsed AML following *1 prior therapies
* De novo AML patients who are are suitable for treatment with decitabine
(patients who are suitable for standard induction chemotherapy and willing to
receive it are excluded)
* Intermediate or high risk MDS or MDS/MPN, including CMML
Arm 4a & 5a:
* Relapsed/refractory AML following *1 prior therapies who have relapsed or
exhibited refractory disease (primary failure)
Arm 4b & 5b:
* Intermediate or High risk MDS patients or MDS/MPN, including CMML who have
failed hypomethylating agent therapy.
Arm 6a
* Newly diagnosed AML patients who are suitable for treatment with azacitidine
Arm 6b :
* Intermediate or high-risk MDS or MDS/MPN, including CMML
2. ECOG performance status 0-1-2
3. Candidate for serial bone marrow aspirate and/or biopsy according to the
institutions guidelines and be willing to undergo the planned bone marrow
aspirate and/biopsy according to protocol.
Exclusion criteria
1. Arms 1-2-3 or Arm 6 : Prior decitabine or hypomethylating agent treatment
for AML or MDS.
2. Impaired cardiac function or clinically significant cardiac disease. See
protocol page 32 for details.
3. HIV, active hepatitis B, C. See protocol page 32-33 for details.
4. Active, known or suspected autoimmune disease. See protocol page 33 for
details.
5. History of, or current drug-induced interstitial lung disease or pneumonitis
grade * 2.
6. Patients who discontinued prior PD-1 or PD-L1 directed therapy due to a
treatment related toxicity should not be included in the PDR001 containing arms
of the study. See protocol page 33 for more details.
7. Patients who discontinued prior TIM-3 directed therapy due to a treatment
related toxicity should not be included in the TIM-3 containing arms of the
study.
8. Treatment with cytotoxic or targeted antineoplastics within 3 weeks of
initiation of study treatment. See protocol page 33 for details.
9. Systemic chronic corticosteroid therapy (* 10 mg/day prednisone or
equivalent) or any immunosuppressive therapy within 7 days of first dose of
study treatment. Topical, inhaled, nasal and ophthalmic steroids are allowed.
10. Live vaccine against infectious disease within 4 weeks of study treatment.
11. Pregnancy, lactation, insufficient contraception for females of
childbearing potential and males.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2016-005060-33-NL |
| ClinicalTrials.gov | NCT03066648 |
| CCMO | NL61755.029.17 |