This study has been transitioned to CTIS with ID 2023-506839-15-00 check the CTIS register for the current data. Primary objectives:# Safety Lead-in Phase: To assess the safety and tolerability, and to establish an RP2D if applicable, of treatment…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
- Renal disorders (excl nephropathies)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Occurrence of Dose-Limiting Toxicity (DLT), Adverse Events (AE), and
discontinuation of study intervention due to an AE.
Objective Response (OR): Complete response (CR) or partial response (PR).
Secondary outcome
# DOR: For participants who demonstrate CR or PR, DOR is defined as the time
from the first documented evidence of CR or PR until disease progression or
death due to any cause, whichever occurs first.
# PFS: The time from the date of randomization to the date of the first
documented PD per RECIST 1.1 by BICR, or death from any cause, whichever occurs
first.
# OS: The time from the date of randomization to the date of death.
# CBR: The percentage of participants who have achieved stable disease (SD) >= 6
months or CR or PR based on assessments by BICR per RECIST 1.1.
Background summary
There were > 400.000 new cases of kidney cancer and > 175.000 deaths due to the
disease reported in 2018 worldwide. Approximately 85% of kidney tumors are
renal cell carcinoma (RCC), RCC comprises approximately 3,8% of all cancers,
and approximately 70% of these have a clear cell (cc) histology.
Since 2005, targeted therapy using VEGF-TKIs and/or anti-VEGF antibodies have
been the mainstay for the treatment of advanced RCC, and agents targeting mTOR
are also used in this setting. More recently, immune checkpoint inhibitors have
become the new revolution in treatment options.
In the EU, for the treatment of 2L ccRCC after 1L treatment with a TKI,
monotherapy with nivolumab or cabozantinib is standard. If 1L treatment is with
nivolumab in combination with ipilimumab, 2L options include any TKI or
lenvatinib in combination with everolimus.
There have been recent advances in the treatment of 1L advanced RCC combining
immunomodulators and/or VEGF-TKI(s), and multiple agents are now available for
the treatment of patients with 2L RCC. However, existing data shows that few
patients experience CR with these agents and nearly all progress. Although
these significant advances have led to a change in the treatment paradigm of
these patients, there remains an unmet need to improve outcomes for both 1L and
2L+ advanced RCC populations. Currently there is no SOC for post PD-(L)1
inhibitors /post VEGF-TKI 2L+ advanced RCC.
There are several drugs currently available for 2L+ therapy in patients with
advanced RCC including nivolumab, cabozantinib, and lenvatinib in combination
with everolimus. These agents have shown benefit in terms of outcome compared
with single agent everolimus, which had previously been the standard 2L
treatment for advanced RCC since the 2008 RECORD 1 study. It is notable that
these studies were all conducted when the SOC for 1L advanced ccRCC were
VEGF-TKIs. No clinical studies have so far been conducted to investigate
subsequent treatment options after 1L treatment with IO/VEGF-TKI either in
combination or in sequence. As a result, there is no SOC for patients with 2L+
post PD-(L)1 inhibitors/post VEGF-TKIs advanced RCC, and there remains an unmet
need to improve treatment outcomes in this population.
Study objective
This study has been transitioned to CTIS with ID 2023-506839-15-00 check the CTIS register for the current data.
Primary objectives:
# Safety Lead-in Phase: To assess the safety and tolerability, and to establish
an RP2D if applicable, of treatment combinations that have not been evaluated
in a separate study.
# Efficacy Phase: To assess the safety and tolerability of each treatment arm
based on the proportion of participants with AEs.
# Efficacy Phase: To evaluate objective response rate (ORR) of each treatment
arm as assessed by Blinded Independent Central Review (BICR) per RECIST 1.1.
Secondary objectives (all in Efficacy Phase):
# To evaluate the duration of response (DOR) as assessed by BICR per RECIST 1.1.
# To evaluate progression free survival (PFS) as assessed by BICR per RECIST
1.1.
# To evaluate overall survival (OS).
# To evaluate clinical benefit rate (CBR) per RECIST 1.1 as assessed by BICR.
Study design
Substudy MK3475-03B from Umbrella research protocol MK3475-U03 is a phase 1b/2,
rolling arm, multicenter, open-label adaptive design study that evaluates the
safety and efficacy of multiple experimental arms for the treatment of advanced
ccRCC in subjects who have previously received at least 1 systemic therapy for
advanced RCC.
This substudy is composed of a specific set of treatment arms, and these arms
are composed of investigational products (IPs). More IP(s) will be added to the
Efficacy Phase of this study after an initial evaluation of safety and
tolerability of the IP(s) has been completed in a separate study or in the
Safety Lead-in Phase of this study.
Intervention
This study has 4 intervention groups with different IP combinations. The
subjects may receive 1 of these IV (intravenous infusion) treatments:
*pembrolizumab or *MK-1308A (quavonlimab + pembrolizumab), 6-weekly for up to 2
years. The subjects may also receive oral treatment (daily) with lenvatinib
and/or belzutifan until disease progression or unacceptable toxicity.
Study burden and risks
By participating in this study, participants will be exposed to invasive
procedures (e.g. biopsy collection, blood collection and CT- or MRI-scans), are
asked to visit the hospital regularly, and receive experimental therapy with
potentially serious side effects. It is unsure if the participants will
directly benefit from the study intervention.
The treatment depends on the group the participant is assigned to. Some of the
treatments have been administered to a large number of oncology patients
(various indications) with a known safety profile. Other treatments have
recently been developed and were administered to < 1.000 participants in
previous studies. All known side effects are included in the written
information provided to the participants, including the expected frequency of
occurrence.
In general, participants must be informed on the nature and extent of the
burden and risks associated with participation, as well as the potential
benefit, by means of the patient information sheet and the explanation from the
investigator.
Waarderweg 39
Haarlem 2031 BN
NL
Waarderweg 39
Haarlem 2031 BN
NL
Listed location countries
Age
Inclusion criteria
# The participant has provided documented informed consent for this study.
# Male or female from 18 years to 120 years at the time of signing the informed
consent form.
# Histologically confirmed diagnosis of locally advanced/metastatic ccRCC (with
or without sarcomatoid features).
# Disease progression on or after systemic treatment for locally advanced or
metastatic RCC with a PD-(L)1 checkpoint inhibitor (in sequence or in
combination with a VEGF-TKI). Criteria for PD-(L)1 checkpoint inhibitor
treatment progression are per protocol.
# Disease progression on or after systemic treatment for locally advanced or
metastatic RCC with a VEGF-TKI (in sequence or in combination with a PD-[L]1
checkpoint inhibitor). Criterion for VEGF-TKI treatment progression is per
protocol.
# Measurable disease by RECIST 1.1 (assessed by a Blinded Independent Central
Review).
# Karnofsky Performance Status >=70% (within 10 days before
randomization/allocation).
# Able to swallow oral medication.
# Presence of an evaluable archival or newly obtained tumor tissue sample for
central analysis.
# Adequate organ function (within 10 days before the start of study
intervention).
# If on bone resorptive therapy, this must be initiated at least 2 weeks before
randomization/allocation.
# Toxic effects of prior therapy are resolved to <= grade 1 (exceptions per
protocol) and for systemic steroid therapy due to an irAE the dose should not
exceed 10 mg daily of prednisone (or equivalent).
# Adequately controlled blood pressure with or without antihypertensive
medications.
# A male participant must agree to use contraception as detailed in the
protocol.
# A female participant is eligible to participate if not pregnant or
breastfeeding, agrees to follow the contraceptive guidance as detailed in the
protocol, or is not of child-bearing potential.
Exclusion criteria
# Prior treatment with pembrolizumab plus lenvatinib in combination.
# Prior treatment with belzutifan or another HIF-2α inhibitor.
# Treated with more than 4 previous systemic anticancer treatment regimens.
# Previously randomized/allocated to study intervention in any substudy of
protocol MK3475-U03.
# Received an investigational product or used an investigational device within
4 weeks before the first dose of study intervention.
# Prior radiotherapy within 2 weeks before the first dose of study intervention
or radiation-related toxicities requiring corticosteroids (exceptions per
protocol).
# Live or live attenuated vaccine within 30 days before the first dose of study
intervention.
# Allogeneic tissue/solid organ transplant.
# Clinically significant cardiovascular disease within 12 months before first
dose of study intervention (details per protocol).
# Prolongation of QTcF interval to >480 ms.
# LVEF below the institutional normal range as determined by MUGA or ECHO.
# Major surgery within 3 weeks before first dose of study intervention.
# Urine protein >=1 g/24 hours.
# History of interstitial lung disease, history of (noninfectious) pneumonitis
that required steroids, or current pneumonitis.
# Symptomatic pleural effusion (details per protocol).
# History of inflammatory bowel disease.
# Preexisting grade >=3 GI or non-GI fistula, or malabsorption due to prior GI
surgery or GI disease.
# Active hemoptysis within 3 weeks prior to the first dose of study
intervention.
# Diagnosis of immunodeficiency or receiving chronic systemic steroid therapy
(or any other form of immunosuppressive therapy) within 7 days before the first
dose of study intervention.
# Known additional malignancy that is progressing or required active treatment
within the past 3 years (exceptions per protocol).
# Known active CNS metastases and/or carcinomatous meningitis (exceptions per
protocol).
# Radiographic evidence of encasement or invasion of a major blood vessel, or
of intratumoral cavitation.
# History of (severe) hypersensitivity reaction to any of the investigational
products included in this study.
# Active autoimmune disease that required systemic treatment in the past 2
years (details and exceptions per protocol).
# Active infection requiring systemic therapy.
# Known history of HIV and/or hepatitis B infection, or known active hepatitis
C infection.
# Pulse oximeter reading <92% at rest, or requiring intermittent or chronic
supplemental oxygen.
# Known psychiatric or substance abuse disorder that would interfere with the
participant*s ability to cooperate with the requirements of the study.
# History or current evidence of any condition, therapy, or laboratory
abnormality that might confound the results of the study, interfere with the
participant*s participation for the full duration of the study, or is not in
the best interest of the participant to participate, in the opinion of the
treating investigator.
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 | CTIS2023-506839-15-00 |
| EudraCT | EUCTR2019-003610-13-NL |
| ClinicalTrials.gov | NCT04626518 |
| CCMO | NL83009.056.22 |