Primary: Dose escalation part: To determine the MTD and/or RP2D of PDR001 in combination with regorafenib in patients with metastatic MSS CRC. Expansion part: To evaluate the efficacy based on overall response rate (ORR) of PDR001 in combination…
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Escalation phase: Incidence of DLT during the first 8 weeks of treatment
Expansion phase: ORR as per RECIST 1.1
Secondary outcome
ORR, adverse events, PK parameters, Antidrug antibodies, OS.
Background summary
Regorafenib is an oral multi-kinase inhibitor that blocks the activity of
several protein kinases, including kinases involved in the regulation of tumor
angiogenesis, oncogenesis, and the tumor micro-environment (PDGFR and FGFR).
Regorafenib has been demonstrated to improve overall survival by decreasing the
risk of death by 33% compared to placebo in patients with pretreated metastatic
colorectal cancer (CRC).
In spite of the treatment improvements and clinical outcome observed with the
approved agents; there is still a need to investigate treatments that could
further improve the benefit risk profile providing longer disease
stabilization, and tumor response together with a tolerable safety profile.
In addition, the subset of patients presenting with CMS4 like subtype are not
likely to respond to available treatments as they typically have a poor
clinical outcome.
For this reason, new treatment combination strategies that modify the immune
contexture with antiangiogenic agents may facilitate the activity of checkpoint
blockade restoring immunogenicity.
This is a Phase Ib study to evaluate the safety and efficacy of the combination
PDR001/regorafenib in previously treated patients with metastatic
Microsatellite Stable (MSS) CRC. The study will have a dose escalation (up to 2
dose levels of regorafenib in combination with PDR001 at a fixed dose) and an
expansion part.
Study objective
Primary:
Dose escalation part: To determine the MTD and/or RP2D of PDR001 in combination
with regorafenib in patients with metastatic MSS CRC.
Expansion part: To evaluate the efficacy based on overall response rate (ORR)
of PDR001 in combination with regorafenib.
Secondary:
Efficacy. Safety and tolerability. Pharmacokinetic (PK) profile,
immunogenicity. Overall survival (OS).
Study design
Multicenter, open label, phase Ib study with a dose escalation part and a dose
expansion part. Treatment with up to 2 dose levels of regorafenib in
combination with PDR001 at a fixed dose until disease progression or
unacceptable toxicity.
Follow-up for safety (5 months) and survival.
Approx. 72 subjects (12 dose escalation part, 60 expansion part).
Intervention
Treatment with PDR001 in combination with regorafenib.
PDR001 (intraveneus) - 400mg per 4 weken
Regorafenib (oraal): startdosering 120mg/ dag. Volgende dosisnieveau:
160mg/dag.
Study burden and risks
Risk: Adverse effects of PDR001 in combination with regorafenib.
Burden: Cycles of 4 weeks. Cycle 1: 3 visits, cycle 2: 2 visits, thereafter 1
visit per cycle.
PDR001: 1 infusion (250 mL) per cycle.
Physical examination: once per cycle (cycle 1: 3 times, cycle 2: 2 times).
Blood tests (5-15 mL/occasion): every visit up to follow-up (cycle 1: 4 times).
Extra blood draws for PK and antidrug antibodies (in total 76 mL) and
biomarkers (in total 225 mL).
Urine testing every visit up to follow-up.
Pregnancy test: every cycle and every visit during safety follow-up.
ECG: 5 times and every 2nd cycle.
CT-/MRI scan: baseline, every 8 weeks thereafter.
Echocardiography: Twice.
Optional examinations: Pharmacogenetic substudy (6 ml blood). Cytokine substudy
in case of adverse events (20 mL blood). Tumor biopsy during study treatment.
Raapopseweg 1
Arnhem 6824 DP
NL
Raapopseweg 1
Arnhem 6824 DP
NL
Listed location countries
Age
Inclusion criteria
1. Metastatic microsatellite stable colorectal adenocarcinoma.
2. Subjects must provide a newly obtained or an archival tumor sample corresponding to CRC diagnosis (primary tumor) with sufficient tissue quality for analysis.
3. Subjects must provide a newly obtained tumor tissue sample from a metastatic site.
4. At least one measurable lesion.
5. Previously treated with two prior regimen as per standard of care and have experienced disease progression.
6. ECOG performance status 0-1
Exclusion criteria
1. High level Microsatellite Instable (MSI-H) colorectal adenocarcinoma as defined per local standard of care testing.
2. Metastatic disease amenable to be resected with potentially curative surgery.
3. Chemotherapy, radiation, or biological cancer therapy within 14 days prior to the first dose of study treatment.
4. Prior treatment with anti-PD-1, anti-PD-L1, anti-PDL2, anti-CTLA-4 antibodies, other checkpoint inhibitors.
5. Any untreated CNS lesion. Exceptions: see protocol page 39.
6. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study treatment.
7. Use of G-CSF and comparable, see protocol page 39 for details.
8. Systemic chronic steroid therapy (* 10mg/day prednisone or equivalent) or any immunosuppressive therapy 7 days prior to start of study treatment.
9. History of severe hypersensitivity reactions to other monoclonal antibodies, see protocol page 39 for details.
10. HIV positive, HBsAg positive, hepatitis positive.
11. Active, known or suspected autoimmune disease or a documented history of autoimmune disease, see protocol page 40 for details.
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 | EUCTR2017-000466-30-NL |
| ClinicalTrials.gov | NCT03081494 |
| CCMO | NL61135.058.17 |