Details
Title A Phase II Clinical Trial to Study the Efficacy and Safety of Pembrolizumab (MK-3475) and Pembrolizumab in Combination with Other Investigational Agents in Subjects with High-risk Non-muscle-Invasive Bladder Cancer (NMIBC) Unresponsive to Bacillus Calmette-Guerin (BCG) Therapy
IRB MRK3814
CC 16-175
Hospital Main Campus
Phase Phase 2
Disease Bladder
Drug Favezelimab, Pembrolizumab, Vibostaolimab
Description
Primary Objectives
Cohort A – Subjects with CIS at baseline (CIS only, Ta+CIS, or T1+CIS)
To evaluate anti-tumor activity of pembrolizumab by evaluating the absence of high-risk NMIBC or progressive disease, as determined by cystoscopy, cytology, biopsy (if applicable), and radiologic imaging by central pathology and radiology review.
Cohort B – Subjects without CIS at baseline (High Grade Ta or Any Grade T1)
To evaluate anti-tumor activity of pembrolizumab by evaluating the absence of high-risk NMIBC or progressive disease, as determined by cystoscopy, cytology, biopsy (if applicable), and radiologic imaging by central pathology and radiology review.
Cohort C – Subjects with CIS at baseline (CIS only, Ta+CIS, or T1+CIS)
To evaluate anti-tumor activity of MK-7684A and MK-4280A by 12-month complete response (CR) rate of high-risk NMIBC, as determined by cystoscopy, cytology, biopsy, and radiologic imaging by central pathology and radiology review.
Secondary Objectives
Cohort A – Subjects with CIS at baseline (CIS only, Ta+CIS, T1+CIS)
To evaluate anti-tumor activity of pembrolizumab by CR rate of any disease.
To evaluate anti-tumor activity of pembrolizumab by Duration of Response (DOR) of high-risk NMIBC and any disease (responders only).
Cohort B – Subjects without CIS at baseline (High Grade Ta or Any Grade T1)
To evaluate anti-tumor activity of pembrolizumab by DFS rate of any disease.
Cohort C – Subjects with CIS at baseline (CIS only, Ta+CIS, T1+CIS)
To evaluate anti-tumor activity of MK-7684A and MK-4280A in the study population
Inclusion Criteria
1. In order to be eligible for participation in this trial, the subject must: be willing and able to provide documented informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
2. Be ≥18 years of age on day of providing documented informed consent.
3. Have a histologically-confirmed diagnosis of high-risk non-muscle invasive (T1, High Grade Ta and/or CIS) transitional cell carcinoma of the bladder. Subjects with tumors of mixed transitional/non-transitional cell histology are allowed, but transitional cell carcinoma must be the predominant histology. Subjects with predominant or exclusively non-transitional cell histology are not allowed. Confirmation of histology, grade and stage will be performed by central review and must be completed during the screening period and prior to enrollment. Subjects with CIS must have CIS present on the tumor sample from the most recent cystoscopy/TURBT. Confirmation of T1 stage tumor requires the presence of detrusor muscle. The tumor samples submitted for central review must be from the most recent TURBT/biopsy available prior to randomization and include both the diagnostic and restaging TURBT/biopsy as applicable.
4. In subjects who have papillary tumors (Ta and T1), a complete TURBT must have been performed, as characterized by:
• Attainment of a visually complete resection of all papillary tumors (Ta and T1)
• Residual CIS not amenable to complete resection is allowed.
• The most recent cystoscopy/TURBT must have been performed within 12 weeks of randomization.
• For Cohort C, subjects with T1 disease should have undergone a restaging TURBT procedure within 12 weeks prior to randomization to confirm complete resection and that the subject continues to meet eligibility criteria.
◦ If restaging TURBT is performed within 12 weeks prior to randomization and the absence of muscle invasive tumor (≥T2) is confirmed by central pathology review, subjects are still eligible even if first TURBT was performed >12 weeks prior to randomization.
◦ Tissue resected during restaging TURBT must be sent to central pathology lab for tumor histology evaluation with results confirming eligibility prior to randomization.
5. Have been treated with adequate BCG therapy and have developed high-risk NMIBC that is unresponsive to BCG therapy.
• Adequate BCG therapy must include:
◦ An induction course with at least 5 instillations of BCG (adequate induction) and
◦ At least 7 instillations of BCG within 9 months of the first instillation of adequate induction course).
• For Cohorts A and B, BCG unresponsive high-risk NMIBC is defined as:
◦ Stage progression at 3 months (±4 weeks) despite adequate induction therapy (eg, Ta to T1, or CIS to T1; note: adequate induction therapy only, defined above, is required in this case); or
◦ High grade T1 disease at the first evaluation after adequate BCG induction or
◦ Persistent high-risk NMIBC at 6 months (±4 weeks) after adequate BCG; or
◦ Recurrent high-risk NMIBC within 9 months of the last BCG instillation despite having received adequate BCG.
Note: The last BCG instillation must have been within 9 months of the most recent HR NMIBC recurrence with which the subject enrolled on study.
• For Cohort C, BCG unresponsive high-risk NMIBC is defined as:
◦ Persistent or recurrent CIS alone or with Ta/T1 within 12 months of completion of adequate BCG therapy.
Note: Stage progression (eg, CIS ± Ta to CIS + T1) at 3 months (±4 weeks) despite adequate induction therapy as defined above are eligible.
Note: The NMIBC recurrence with which the subject was deemed BCG-unresponsive does not have to be the most recent recurrence with which the subject enrolls into the study.
6. Have elected not to undergo, or are considered ineligible for radical cystectomy, as determined by the treating physician. Reasons for ineligibility or refusal of radical cystectomy should be discussed with the subject as part of the informed consent process and should be captured on the appropriate case report form. Ineligibility factors for radical cystectomy may include, but are not limited to:
• Cardiovascular disease (eg, recent acute coronary syndrome, arrhythmia, heart failure)
• Chronic obstructive pulmonary disease that would preclude a safe surgical procedure, as determined by the treating physician
• Poor performance status (eg, ECOG >2)
• Prior major abdominal and pelvic surgery that would preclude a safe surgical procedure, as determined by the treating physician
7. Have provided tissue for biomarker analysis from the most recent cystoscopy/TURBT procedures from which tumor sample is available. If submitting unstained cut slides, freshly cut slides should be submitted to the testing laboratory within 14 days from when the slides are cut. See Section 7.1.2 for an explanation.
Note: It is preferred that the sample for PD-L1 analysis is taken from the most recent TURBT (ie, the same time point submitted for histology review). However, if there is not sufficient tissue, a sample can be provided from an earlier TURBT taken within 12 weeks before first dose of study treatment.
8. Have a performance status of 0, 1 or 2 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale, as assessed within 28 days prior to treatment initiation. A maximum of 5% of subjects with ECOG 2 status will be enrolled into the study (for Cohorts A and B only).
9. Have adequate organ function as defined in Table 1. All screening labs should be performed within 28 days prior to treatment initiation.
• Subjects may not have received transfusion of packed red blood cells (PRBCs) or platelets within 4 weeks prior to screening.
10. A female subject is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
• Is not a WOCBP OR
• Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), with low user dependency, or be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long-term and persistent basis), as described in Appendix 12.9 during the intervention period and for at least 120 days after the last dose of study intervention. The investigator should evaluate the potential for contraceptive method failure (ie, noncompliance, recently initiated) in relationship to the first dose of study intervention.
- A WOCBP must have a negative highly sensitive pregnancy test (urine or serum as required by local regulations) within 24 hours for urine or within 72 hours for serum before the first dose of study intervention.
- If a urine test cannot be confirmed as negative (eg, an ambiguous result), a serum pregnancy test is required. In such cases, the subject must be excluded from participation if the serum pregnancy result is positive.
- Additional requirements for pregnancy testing during and after study intervention are located in Section 7.1.3.1.1.
- The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
- Contraceptive use by females should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies. If the contraception requirements in the local label for any of the study drugs is more stringent than the requirements above, the local label requirements should be followed.
Exclusion Criteria
1. Has centrally assessed muscle invasive (ie, T2, T3, T4) locally advanced non-resectable or metastatic urothelial carcinoma.
2. Has centrally assessed concurrent extra-vesical (ie, urethra, ureter or renal pelvis) non-muscle invasive transitional cell carcinoma of the urothelium.
3. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigational device within 4 weeks of the first dose of treatment.
4. Has undergone any intervening intravesical chemotherapy or immunotherapy from the time of most recent cystoscopy/TURBT to starting trial treatment. (Note: A single dose of intravesical treatment given as part of the most recent cystoscopy/TURBT, during the screening period, such as with chemotherapy as per local/regional practices, is acceptable.)
5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to Cycle 1, Day 1 or who has not recovered (ie, ≤Grade 1 or at baseline) from adverse events due to a previously administered agent.
• Subjects with ≤Grade 2 neuropathy or ≤Grade 2 alopecia are an exception to this criterion and may qualify for the study.
• If subject has undergone major surgery, they must have recovered adequately from the toxicity and/or complications from the intervention prior to starting therapy.
6. Has a known additional malignancy that has had progression or has required active treatment in the last 3 years. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer. A history of prostate cancer that was treated with definitive intent (surgically or through radiation therapy) is acceptable, provided that the following criteria are met: Stage T2N0M0 or lower with a Gleason score ≤7 and prostatic-specific antigen (PSA) undetectable for at least 1 year while off androgen deprivation therapy that was either treated with definitive intent or untreated in active surveillance that has been stable for the past year prior to study allocation.
7. Has present or progressive accumulation of pleural, ascitic, or pericardial fluid requiring drainage or diuretic drugs (exception for use in hypertension) within 2 weeks before randomization/study allocation for Cohort C.
8. Has severe hypersensitivity (≥Grade 3) to pembrolizumab (all cohorts), MK-7684A (Cohort C Arm 1), MK-4280A (Cohort C Arm 2), and/or any of their excipients.
9. Has an active autoimmune disease that has required systemic treatment in past 2 years (ie, with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc) is not considered a form of systemic treatment.
10. Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of the study intervention. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.
11. Has a history of (noninfectious) pneumonitis/interstitial lung disease that required steroids or has current pneumonitis.
12. Has an active infection requiring systemic therapy, including active or intractable UTI in the last month.
13. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
14. Has a known psychiatric or substance abuse disorder that would interfere with the subject’s ability to cooperate with the requirements of the trial.
15. Is pregnant or breastfeeding, or expecting to conceive within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.
16. Has received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2 agent, or with an agent directed to another coinhibitory T-cell receptor (eg, CTLA-4, OX-40, CD137).
17. Has received previous treatment with another agent targeting the TIGIT and/or LAG3 receptor pathway (Cohort C only).
18. Has a known history of Human Immunodeficiency Virus (HIV) (HIV-1/2 antibodies). No HIV testing is required unless mandated by local health authority.
Note (for Cohort C): HIV-infected subjects who have well controlled HIV on ART are eligible, defined as:
• Subjects on ART must have a CD4+ T-cell count >350 cells/mm3 at the time of Screening.
• Subjects on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 or the LLOQ (below the limit of detection) using the locally available assay at the time of Screening and for at least 12 weeks before Screening.
• It is advised that subjects must not have had any AIDS-defining opportunistic infections within the past 12 months.
• Subjects on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks before study entry (randomization/allocation).
19. Has known active Hepatitis B (eg, HBsAg reactive) or Hepatitis C (eg, HCV RNA [qualitative] is detected).
Note (for Cohort C): Subjects who are HBsAg positive are eligible if they have received HBV antiviral therapy for at least 4 weeks and have undetectable HBV viral load prior to randomization. Subjects should remain on antiviral therapy throughout study intervention and follow local guidelines for HBV antiviral therapy postcompletion of study intervention. No testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
20. Has received a live virus vaccine within 30 days of planned start of trial treatment. Refer to Section 5.5.2 for information on COVID-19 vaccines.
21. Has had an allogeneic tissue/solid organ transplant.
