This study has been transitioned to CTIS with ID 2023-503905-12-00 check the CTIS register for the current data. The main objectives for this study are: - To assess the safety and tolerability of the combination of pembrolizumab and lenvatinib and…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary outcome to asses safety and tolerability
- Dose-limiting toxicity (DLTs) (Safety Lead-in Phase only).
- Adverse events (AEs).
- Study intervention discontinuations due to AEs.
Primary outcome to evaluate ORR
- Objective response (OR): complete response (CR) or partial response (PR)
Secondary outcome
- DOR: the time from first documented evidence of CR or PR until either disease
progression or death due to any cause, whichever occurs first.
- Disease control (DC): best overall response of CR, PR, or stable disease (SD)
after >=6 weeks (the start of the window for the first scheduled scan).
- PFS: the time from first day of study intervention to the first documented
disease progression or death due to any cause, whichever occurs first.
- OS: the time from first day of study intervention to death due to any cause.
- OR, DOR, DC, and PFS
Background summary
The immunemodulating effect of lenvatinib may result in a potent combination
effect with PD-1/L1 signal inhibitors. Based on the preclinical findings,
pembrolizumab and lenvatinib are being investigated in multiple solid tumors in
Phase 2 and Phase 3 clinical studies. This combination has shown clinical
efficacy in several tumor types, showed a manageable safety profile, and is
currently approved for endometrial cancer (non-MSI-H) under accelerated
approval.
The scientific rationale for combining belzutifan with pembrolizumab and
lenvatinib stems
from the role of hypoxia signaling and HIF-2α in multiple downstream events.
The role of HIF-2α in hypoxia signaling and activation of downstream pathways
related to cell survival, angiogenesis, metastases, and tumor progression is
relevant in HCC, and a synergistic effect is expected with the addition of
belzutifan to the doublet by inhibition of pathogenic angiogenesis,
upregulation of immune regulation response by decrease in TAMs, and overcoming
resistance to TKIs due to the role of HIF-2α overexpression in mediating
resistance to VEGFR TKIs such as sorafenib.
The clinical rationale for studying the triplet of belzutifan, pembrolizumab
and lenvatinib in
the proposed indications come from promising doublet (pembrolizumab plus
lenvatinib)
antitumor activity and manageable safety profile; the addition of a
HIF-2α inhibitor is expected to improve antitumor activity and clinical
responses based on
the scientific rationale proposed above.
The tumor types included in this study are Hepatocellular Cancer (HCC),
Colorectal Cancer (CRC), Pancreatic Ductal Adenocarcinoma (PDAC), and Biliary
Tract Cancer (BTC).
For HCC the importance of angiogenesis pathway, efficacy of immune checkpoint
inhibitors, potential for synergism from combination with HIF-2α inhibitor in
inhibiting pathogenic angiogenesis, and overcoming resistance to TKIs provides
rationale to study the efficacy and safety of the triplet combination in the 1L
setting.
For CRC there is a high unmet need for effective treatment options in
metastatic CRC after progressing on at least 2 prior therapies (3L or beyond)
especially in non-MSIH/dMMR CRC, and novel treatment combinations are in need.
Overall the benefit for PDAC from later-line therapies after 1L therapy is very
limited and most patients die of their disease (the ORR in 2L/3L setting is
approximately 15%) [Wang-Gillam, A., et al 2016], hence there is huge unmet
need for novel therapies in the 2L or later setting for PDAC.
While there are promising new targeted therapies becoming available for BTC
with genomic alterations such as pemigatinib (for FGFR2 alterations), with good
antitumor activity in a small subset of patients, a vast majority of patients
do not have effective treatment options and hence there is a high unmet medical
need for novel treatment combinations in the 2L or later-line treatment setting
in advanced BTC.
Study objective
This study has been transitioned to CTIS with ID 2023-503905-12-00 check the CTIS register for the current data.
The main objectives for this study are:
- To assess the safety and tolerability of the combination of pembrolizumab and
lenvatinib and belzutifan.
- To evaluate the confirmed objective response rate (ORR) per RECIST 1.1 as
assessed by blinded independent central review (BICR)
Study design
This is a phase 2, nonrandomized, open-label, multisite study of pembrolizumab
plus lenvatinib in combination with belzutifan with participant cohorts in CRC
(non-MSI-H/dMMR), HCC, PDAC, BTC. esophageal SCC.
Approximately 240 participants (30 per cohort) who meet all inclusion criteria
and none of the exclusion criteria will be enrolled (Expansion
by up to 70 additional participants per tumor type) including participants from
the Safety Lead-in Phase at the chosen dose level.
A Safety Lead-in Phase will be conducted using the mTPI design (target DLT rate
of 30%) for:
• HCC participants separately (total N will depend on number of dose levels
assessed but should include up to 10 DLT-evaluable participants at Dose Level 0
or a dose level that will be chosen to proceed) and,
• CRC, PDAC or BTC participants (pooled; total N will depend on number of dose
levels assessed but should include up to 15 DLT-evaluable participants at Dose
Level 0 or a dose level that will be chosen to proceed)
Intervention
All cohorts will receive: Q6W 400mg Pembrolizumab, daily 20mg Lenvatinib (for
HCC, 8mg if <60kg or 12mg if >60kg) and daily 120mg Belzutifan.
Study burden and risks
It cannot be guaranteed that participants in clinical studies will directly
benefit from
treatment during participation, as clinical studies are designed to provide
information about
the safety and effectiveness of an investigational medicine.
As described in the Section 2.1 of the protocol, the combination of
pembrolizumab and lenvatinib has shown promising efficacy signals in HCC, CRC
(non-MSI-H/dMMR), and BTC patients. The addition of the HIF-2α inhibitor,
belzutifan, to improve on the response rates in these high unmet need
indications, including PDAC, is justified by the role HIF-2α plays in tumor
hypoxia signaling, and downstream effects on promotion of angiogenesis, cell
proliferation, metastasis, and a role in conferring resistance to TKIs (eg,
HCC). We expect that the novel triple combination of belzutifan, pembrolizumab,
and lenvatinib may improve ORR in the tumor types being studied over the
pembrolizumab/lenvatinib combination and produce durable clinical benefit.
Currently there are no clinical data for the triplet combination of
pembrolizumab, lenvatinib, and belzutifan in any tumor type and there are no
clinical data for the combination of pembrolizumab plus lenvatinib in PDAC.
However, potential risks of this novel combination may be increased toxicity,
intolerability, or unanticipated adverse drug reactions. Some of these expected
Aes are anemia, hypoxia
and hepatotoxicity. Putative risks associated with combination of pembrolizumab
and lenvatinib plus belzutifan, in addition to the known safety profile with
each agent alone, may be hypoxia and anemia with increased frequency and/or
severity.
Waarderweg 39
Haarlem 2031 BN
NL
Waarderweg 39
Haarlem 2031 BN
NL
Listed location countries
Age
Inclusion criteria
1. Diagnosis of one of the following advanced (unresectable and/or metastatic)
solid tumors, documented by histopathology or cytopathology:
- HCC
- CRC
- PDAC
- BTC
- ESCC
2. Disease progression on or since the most recent treatment (does not
applicable to newly diagnosed unresectable or metastatic HCC).
3. Measurable disease per RECIST v1.1 as assessed locally (by investigator) and
verified by BICR.
4. Submission of an archival tumor tissue sample or newly obtained core or
excisional biopsy of a tumor lesion not previously irradiated.
5. Male or female, at least 18 years of age.
6. Male participants are abstinent from heterosecual intercourse or agree to
follow contraceptive guidance during and for at least 7 days after last dose of
study intervention with belzutifan and lenvatinib.
7. Female participants are not pregnant or breastfeeding, not a woman of
child-baering potential (WOCBP) or is a WOCBP and agrees to follow
contraceptive guidance during the intervention period and for at least 120 days
after the last dose of pembrolizumab or for at least 30 days after last dose of
lenvatinib or belzutifan, whichever occurs last after the last dose of study
intervention.
8. ECOG performance status of 0 to 1 within 7 days of before the start of study
intervention.
9. Adequate organ function
10. Adequately controlled blood pressure with or without antihypertensive
medications.
Additional specific inclusion criteria are applicable per cohort, please refer
to the protocol
Exclusion criteria
1. Unable to swallow orally administered medication or has a significant GI
disorder that may affect study intervention absorption.
2. History of a second malignancy that is progressing or has required active
treatment within 3 years.
3. A pulse oximeter reading <92% at rest, or requirement of intermittent
supplemental oxygen / or requires chronic supplemental oxygen.
4. Presence of Centeral nervous system (CNS) metastases and/or carcinomatous
meningitis.
5. Clinically significant cardiovascular disease within 6 months of first dose
of study intervention,
6. Prolongation of QTc interval to >480 ms.
7. Urine protein >=1 g/24 hours.
8. Symptomatic pleural effusion unless clinically stable after treatment.
9. Preexisting >= Grade 3 GI or non-GI fistula.
10. Moderate to severe hepatic impairment (Child-Pugh B or C).
11. Clinically significant history of bleeding within 3 months before
screening.
12. Presence of serious active nonhealing wound/ulcer/bone fracture
13. Requirement for hemodialysis or peritoneal dialysis
14. Received colony-stimulating factors or transfusion within 28 days before
study treatment initiation.
For the complete list, please refer to the protocol.
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 |
|---|---|
| EU-CTR | CTIS2023-503905-12-00 |
| EudraCT | EUCTR2020-005-007-4-NL |
| CCMO | NL77365.028.21 |