Sitagliptin With Pembro in RCC and Melanoma

Official title

A Phase 1b Study of Sitagliptin in Combination With Pembrolizumab in Refractory or Relapsed Advanced Renal Cell Carcinoma and Melanoma

Overview

This study is testing whether adding the drug sitagliptin to the standard immunotherapy pembrolizumab is safe and may help people with advanced melanoma or advanced renal cell carcinoma (kidney cancer) whose cancer has stopped responding to prior PD-1 or PD-L1 immunotherapy. The study has two parts. In the first part, small groups of participants will receive different doses of sitagliptin along with a fixed dose of pembrolizumab. This helps researchers find the highest dose of sitagliptin that can be given safely. In the second part, more participants will receive the safest dose to see how well the drug combination works against their cancer.

Interventions

• Drug Sitagliptin
  An oral dipeptidyl peptidase-4 (DPP-4) inhibitor administered once daily at escalating dose levels adjusted for renal function, used to evaluate safety and potential immunomodulatory and anti-tumor activity in combination with pembrolizumab
• Drug Pembrolizumab
  A programmed death-1 (PD-1) immune checkpoint inhibitor administered as a 200 mg intravenous infusion every 3 weeks, used as standard-of-care immunotherapy in advanced melanoma and renal cell carcinoma

Primary outcome measures

• Dose-Limiting Toxicities (DLTs) [Time frame: During cycle 1 (cycle 1 is 21 days)]
• Overall Response Rate (ORR) [Time frame: From treatment initiation up to 60 months or until disease progression or discontinuation, whichever occurs first, assessed every 12 weeks]

Secondary outcome measures (2)

• Disease Control Rate (DCR) [Time frame: From treatment initiation up to 60 months or until disease progression or discontinuation, whichever occurs first, assessed every 12 weeks.]
• Progression-Free Survival (PFS) [Time frame: From treatment initiation until documented disease progression or death from any cause, whichever occurs first, assessed up to 60 months.]

Eligibility criteria

Inclusion criteria

• Histologically and/or cytologically confirmed unresectable metastatic renal cell carcinoma with clear cell component with no neuroendocrine differentiation component) or unresectable metastatic melanoma (excluding uveal or mucosal melanoma) that have progressed on treatment with an anti-PD-1/PD-L1 mAb administered either as a monotherapy, or in combination with other immune checkpoint inhibitors or other therapies. Progression on treatment with an anti-PD-1/PD-L1 mAb is defined by meeting all of the following criteria:

• Has received at least 2 doses of an approved anti-PD-1/PD-L1 mAb
• Has demonstrated disease progression after anti-PD-1/PD-L1 mAb as defined by RECIST v1.1. The initial evidence of disease progression (PD) is confirmed by a second assessment no less than 4 weeks from the date of the first documented PD
• Progressive disease has been documented within 12 weeks from last dose of anti-PD-1/PD-L1 mAb (refractory disease) or ≥12 weeks from last dose of anti-PD-1/PD-L1 mAb (late relapse)
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2
• Measurable disease meeting the following criteria:

• At least 1 lesion of ≥10mm in the longest diameter for a non-lymph node or ≥15mm in the short-axis diameter for a lymph node that is serially measurable according to RECIST v1.1 using computerized tomography/magnetic resonance imaging (CT/MRI)
• Lesions that have had external beam radiotherapy (EBRT) or loco-regional therapies such as radiofrequency (RF) ablation must show subsequent evidence of substantial size increase to be deemed a target lesion
• Aged 18 years and older
• The participant is capable of understanding and complying with the protocol requirements and has signed the informed consent document
• Participants must have recovered adequately from any toxicity and/or complications from major surgery prior to starting therapy to < Grade 1 CTCAE unless clinically insignificant and/or stable on supportive therapy.
• No active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with the use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine or physiological corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment
• Women of childbearing potential (WOCBP) - defined as females who have experienced menarche, have not undergone permanent surgical sterilization (i.e., hysterectomy, bilateral oophorectomy, or bilateral tubal ligation), and are not postmenopausal (no menses for ≥12 consecutive months without an alternative medical cause) - must meet all of the following criteria:

• Have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication.

• If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test must be performed and must be negative prior to enrollment.
• Agree to use at least one highly effective method of contraception during the study and for a minimum of 4 months after the last dose of pembrolizumab.

Acceptable highly effective methods include:

• Combined (estrogen- and progestogen-containing) hormonal contraception (oral, intravaginal, or transdermal)
• Progestogen-only hormonal contraception (oral, injectable, or implantable)
• Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)
• Bilateral tubal occlusion
• Vasectomized partner (if confirmed as the sole sexual partner)
• Complete sexual abstinence (only if this is the participant's usual and preferred lifestyle)
• Male participants must:

• Use a condom with spermicide during the study and for at least 4 months after the last dose of pembrolizumab, and
• Ensure that their female partners of childbearing potential use an additional highly effective method of contraception during this period.
• Able to swallow pills
• Adequate archival tissue sample ( 5-10 slides at 5µm) of at least one tumor lesion is mandatory. If archival tissue is not available, Participant must agree to a new biopsy sample.

Exclusion criteria

A patient meeting any of the following criteria is not eligible to participate in this study:

• Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial.
• Participants with renal cell carcinoma with histologic/cytologic component of neuroendocrine differentiation
• Participants with uveal or mucosal melanoma
• Participants with both renal cell carcinoma and melanoma
• Participants with diabetes mellitus requiring insulin therapy or sulfonylurea
• Participants taking oral antihyperglycemics (e.g., metformin, DPP-4 inhibitor, SGLT-2 inhibitor) for any cause within 3 months of starting study drug
• Participants with documented history of hypoglycemia requiring medical intervention, oral or intravenous carbohydrate ( glucose, dextrose, fruit juice, or any form of glucagon) or who in the opinion of the investigator are not suitable to receive sitagliptin
• Taking digoxin within 6 months of starting study drug
• Known intolerance or history of severe hypersensitivity reaction (such as anaphylactic shock or angioedema) to sitagliptin or monoclonal antibody
• Prior anticancer treatment within 28 days (or 5 times the half-life, whichever is shorter) or any investigational agent within 30 days prior to the first dose of study treatment.
• Gastrointestinal malabsorption, gastrointestinal anastomosis, or any other condition that might affect the absorption of sitagliptin
• Active uncontrolled infection requiring systemic therapy.
• Participant is known to be positive for Human Immunodeficiency Virus (HIV), Hepatitis B or Hepatitis C
• History of organ allograft (participant has had an allogenic tissue/solid organ transplant)
• Biologic response modifiers (e.g., granulocyte colony-stimulating factor) within 4 weeks before study entry. Chronic erythropoietin therapy is permitted provided that no dose adjustments were made within 2 months before the first dose of study treatment
• Any medical or other condition which, in the opinion of the investigator, would preclude participation in a clinical study
• Females who are pregnant or breastfeeding
• Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of study treatment. The use of physiologic doses of corticosteroids (up to 7.5mg/d of prednisone or equivalent) may be approved after consultation with the sponsor
• Has history of (non-infectious) pneumonitis that required steroids, or current pneumonitis
• Has received a live-virus vaccination within 30 days of planned treatment start. Seasonal flu vaccines that do not contain live virus are permitted

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Non-randomized

Model

Parallel assignment

Masking

Open label

Primary purpose

Treatment

Study locations

United States · 1 center

• University of Iowa — Iowa City

Identifiers

NCT: NCT07634380 · 202512227

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗