This study has been transitioned to CTIS with ID 2023-505023-31-00 check the CTIS register for the current data. 1) To compare disease-free survival (DFS) as assessed by investigator for participants treated with belzutifan plus pembrolizumab versus…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1) To compare disease-free survival (DFS) as assessed by investigator for
participants treated with belzutifan plus pembrolizumab versus those receiving
placebo plus pembrolizumab
Secondary outcome
- To compare overall survival (OS)
- To compare the safety and tolerability profiles
- To compare measures of disease recurrence-specific survival (DRSS)
- To evaluate change from baseline in health-related quality of life (HRQoL)
and symptoms
Background summary
40% of patients with locally advanced (T2-T4) RCC experience recurrence after
surgery. In addition, These patients have a higher incidence of metastasis at
the time of disease recurrence and the estimated 5-year survival of patients
with localized low-, intermediate-, and highrisk RCC is approximately 92%, 67%,
and 44% (respectively), and decreases to 12% in metastatic RCC patients. As
such, effective adjuvant therapy for RCC is an unmet medical need for patients
with features that confer a high risk of recurrence. The success of targeted
therapies and combination therapies in the treatment of advanced/metastatic RCC
led to the interest in testing their efficacy in the adjuvant setting as well.
Results of previous studies (KY564) demonstrated a direct evidence of clinical
benefit for pembrolizumab monotherapy in the adjuvant setting in patients with
RCC following nephrectomy. Based on these findings and the positive
risk-benefit profile, pembrolizumab monotherapy offers an effective and
tolerable new therapeutic option for these patients. However, there is still an
unmet need to further optimize threatment strategies. The combination of
pembrolizumab with belzutifan, a HIF 2-alfa inhibitor, is likely to enhance the
therapeutic benefit providing increased activity over the pembrolizumab alone
treatment in patients with ccRCC
Pembrolizumab is a potent humanized IgG4 monoclonal antibody (mAb) with high
specificity of binding to the programmed
cell death 1 (PD-1) receptor, thus inhibiting its interaction with ligand PD-L1
and ligand PD-L2.The PD-1 receptor-ligand interaction is a major pathway
hijacked by tumors to suppress immune control. The normal function of PD-1,
expressed on the cell surface of activated T- cells under healthy conditions,
is to down-modulate unwanted or excessive immune responses, including
autoimmune reactions. As a consequence, the PD-1/PD-L1 pathway is an attractive
target for adjuvant treatment for clear cell renal cell carcinoma post
nephrectomy.
Patients with RCC have a defective VHL protein. As a result, HIF-2α cannot bind
to VHL and there is no degradation of HIF-2α . Instead, HIF-2α stabilizes and
binds with HIF-1β in the cell nucleus. This activates various oncogenes such as
cell proliferation, cell survival and angiogenesis. Belzutifan is a molecule
that can bind to HIF-2α with high specificity . Consequently, Belzutifan blocks
the heterodimerization with HIF-1β. The connection between Belzutifan and
HIF-2α thereby inhibits the transcription of these oncogenes.
Study objective
This study has been transitioned to CTIS with ID 2023-505023-31-00 check the CTIS register for the current data.
1) To compare disease-free survival (DFS) as assessed by investigator for
participants treated with belzutifan plus pembrolizumab versus those receiving
placebo plus pembrolizumab
Study design
This is a multicenter, double-blind, randomized Phase 3 study to evaluate the
efficacy and safety of Belzutifan (MK-6482) plus pembrolizumab (MK-3475) versus
Placebo plus pembrolizumab, in the adjuvant treatment of clear cell renal cell
carcinoma (ccRCC) Post-nephrectomy. to investigate.
Worldwide, approximately 1600 patients will be included. In the Netherlands
this will be 60 patients. Screening procedures must be completed within 42 days
prior to treatment. After this screening period, the patient will be randomized
1:1 into one of two treatment groups:
1) Belzutifan + pembrolizumab
2) Placebo + pembrolizumab
A cycle lasts 42 days (6 weeks). A patient can receive up to 9 doses of
pembrolizumab (9 cycle, 54 weeks). Belzutifan is used daily. After the end of
treatment, each patient will be monitored for pregnancy and adverse events.
All patients are followed up until death, withdrawal of consent or the end of
the study.
Intervention
2 treatment groups
1) Belzutifan (120 mg oral, every day for 54 weeks) + Pembrolizumab (400 mg
infusion, every 6 weeks up to a maximum of 9 doses)
2) Placebo (0 mg, every day for 54 weeks) + Pembrolizumab (400 mg, every 6
weeks up to a maximum of 9 doses)
Study burden and risks
For this study, patients will be subjected to invasive procedures such as blood
collection, CT-MRI or bone scans, physical exams, possibly confrontational
questionnaires, and patients will be asked to visit the hospital regularly.
Patients will be administered with different medicines, during six-week cycles
up to a maximum of 9 treatments with pembrolizumab and 1 daily dosis of
pemrbolizumab (up to 54 weeks).
It cannot be guaranteed that participants in clinical studies will directly
benefit from study intervention during participation, as clinical studies are
designed to provide information about the safety and effectiveness of an
investigational medicine. Pembrolizumab and Belzutifan have been administered
in a large number of cancer participants with a well characterized safety
profile and pemrbolizumab has received
regulatory approval for multiple malignancies. Overall, pembrolizumab and
belzutifan are well tolerated in previous studies. However, potential risks of
this novel combination may beincreased toxicity, intolerability, or
unanticipated adverse drug reactions
Waarderweg 39
Haarlem 2031 BN
NL
Waarderweg 39
Haarlem 2031 BN
NL
Listed location countries
Age
Inclusion criteria
The below mentioned inclusion criteria are the most important ones. A complete
list of specific inlcusion criteria can be found in the protocol.
1. Has a histologically or cytologically confirmed diagnosis of RCC with clear
cell component per AJCC (8th Edition), with or without sarcomatoid features.
2. Has intermediate-high risk, high risk, or M1 NED RCC
3. Has undergone complete resection of the primary tumor (partial or radical
nephrectomy) and complete resection of solid, isolated, soft tissue metastatic
lesion(s) in M1 NED participants.
4. Must have undergone a nephrectomy and/or metastasectomy <=12 weeks prior to
randomization
5. Must be tumor-free before randomization as assessed by the investigator and
verified by BICR
6. Must have provided tissue per any of the following:
• Nephrectomy only: tissue from nephrectomy (required).
• Synchronous M1 NED: tissue from nephrectomy (required) and tissue from
metastasectomy (if available).
• Metachronous M1 NED: tissue from metastasectomy (required) and tissue from
nephrectomy (if available).
7. Is male or female, at least 18 years of age, at the time of signing the
informed consent.
8. Has ECOG performance status of 0 to 1 within 10 days before randomization.
9. Agrees to the following during the intervention period and for at least the
time needed to eliminate the study intervention after the last dose of study
intervention. The length of time required to continue contraception for the
study intervention is as follows:
- Belzutifan/placebo - at least 7 days after the last dose
• Abstains from heterosexual intercourse as their preferred and usual lifestyle
and agree to remain abstinent OR
• Uses contraception unless confirmed to be azoospermic as detailed
10. A female participant is eligible to participate if she is not pregnant or
breastfeeding
11. The participant has provided documented informed consent/assent for the
study. The participant may also provide consent/assent for FBR.
12. Has adequate organ function.
Exclusion criteria
The below mentioned exclusion criteria are the most important ones. A complete
list of specific inlcusion criteria can be found in the protocol.
1. Has had a major surgery, other than nephrectomy plus resection of
preexisting metastases for M1 NED participants, within 4 weeks prior to
randomization.
2. 2. Has residual thrombus post nephrectomy in the vena renalis or vena cava.
3. 3. Has any of the following:
• Pulse oximeter reading <92% at rest, or
• Requires intermittent supplemental oxygen, or
• Requires chronic supplemental oxygen.
4. Has clinically significant cardiovascular disease within 6 months from first
dose of study intervention,
5. Has other clinically significant disorders such as:
• Serious active nonhealing wound/ulcer/bone fracture
• Requirement for hemodialysis or peritoneal dialysis
6. Has preexisting brain or bone metastatic lesions.
7. Has received colony-stimulating factors (eg, G-CSF, GM-CSF) or recombinant
EPO or transfusion within 28 days before study intervention
initiation.
8. Is unable to swallow orally administered medication or has a history or
current evidence of a GI condition or impaired liver function or diseases that
in the opinion of the investigator may significantly alter the absorption or
metabolism of oral study intervention.
9. Has a severe hypersensitivity (Grade >=3) reaction to belzutifan/placebo or
pembrolizumab and/or any of their excipients
10. Has received prior systemic therapy for RCC
11. Has received prior radiotherapy for RCC.
12. Has received a live or live-attenuated vaccine within 30 days before the
first dose of study intervention.
13. Is currently participating in or has participated in a study of an
investigational agent or has used an investigational device within 4 weeks
before the first dose of study intervention
14. Has a diagnosis of immunodeficiency or is receiving chronic systemic
steroid therapy or any other form of immunosuppressive therapy within 7 days
prior the first dose of study intervention
15. Has a known additional malignancy (other than RCC treated with nephrectomy
and/or metastasectomy) that is progressing or has required active treatment
within the past 3 years.
16. Has an active autoimmune disease that has required systemic treatment in
past 2 years
17. Has a history of (noninfectious) pneumonitis/interstitial lung disease that
required steroids or has current pneumonitis/interstitial lung disease.
18. Has an active infection, requiring systemic therapy.
19. Has a known history of HIV infection, a known history of Hepatitis B or
known active Hepatitis C virus infection
20. Has a history or current evidence of any condition, therapy, laboratory
abnormality, or other circumstance that might confound the results of the study
or interfere with the participant's participation for the full duration of the
study.
21. Has a known psychiatric or substance abuse disorder that would interfere
with the participant's ability to cooperate with the requirements of the study
22. Has had an allogenic tissue/solid organ transplant.
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 | CTIS2023-505023-31-00 |
| EudraCT | EUCTR2021-003436-92-NL |
| CCMO | NL79608.028.21 |