A Phase I/II, Open-Label Study to Investigate the Safety, Clinical Activity, Pharmacokinetics, and Pharmacodynamics of GSK3145095 Administered Alone and in Combination With Anticancer Agents Including Pembrolizumab in Adult Participants With Selected Advanced Solid Tumors

Plain English Summary

First-time-in-human (FTIH) Study of GSK3145095 Alone and in Combination With Other Anticancer Agents in Adults With Advanced Solid Tumors is a Phase 2 clinical trial sponsored by GlaxoSmithKline studying Neoplasms, Pancreatic. This trial tested a new drug called GSK3145095, alone or with other cancer treatments like pembrolizumab. It was for adults with advanced solid tumors, specifically pancreatic cancer, non-small cell lung cancer, triple-negative breast cancer, or melanoma. Participation involved taking the study drug and undergoing regular medical assessments, including biopsies. Due to the trial's termination, there are no alternative treatments being investigated within this specific study. The trial aims to enroll 8 participants.

Official Summary

In an unbiased CRISPR screen, RIPK1 was identified as a top gene contributing to immunotherapy resistance. In addition, RIPK1 has been reported to drive pancreatic oncogenesis. In murine models, inhibition of RIPK1 kinase activity in the pancreatic tumor microenvironment leads to the replacement of tumor-permissive myeloid infiltrates with innate cells that promote an effective antitumor response by adaptive cells. The investigators hypothesize that inhibition of RIPK1 in human pancreatic cancer subjects will modulate the immune infiltrate to sensitize tumors to checkpoint blockade.

Who Can Participate

Here is what you need to know about eligibility for this trial. Adults aged 18 and older with specific advanced cancers that have not responded to standard treatments. Patients must have measurable disease and a good general health status (ECOG performance status 0-1). Individuals who have previously received certain types of immunotherapy or drugs affecting tumor-associated macrophages cannot participate. Women who are pregnant or breastfeeding, and men and women not using highly effective contraception, are excluded. This trial is studying Neoplasms, Pancreatic, so participants generally need a confirmed diagnosis.

What They're Measuring

The primary outcomes measured the safety of the drug by tracking side effects and dose-limiting toxicities, meaning how well patients tolerated the treatment. The specific primary outcome measures are: Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 (Up to Day 95); Number of Participants With Non-serious AEs and SAEs-Part 2 (Up to 2 years and 90 days); Number of Participants With AEs by Severity Grades-Part 1 (Up to Day 95); Number of Participants With AEs by Severity Grades-Part 2 (Up to 2 years and 90 days); Number of Participants With Dose-limiting Toxicities (DLTs)-Part 1 (Up to Day 28). These endpoints are how researchers determine whether the treatment is effective and will form the basis of any future regulatory submissions.

About This Phase

This trial is in Phase 2, which tests whether the treatment actually works against the target condition. Phase 2 trials involve 100-300 patients and continue to monitor safety while evaluating effectiveness. This phase often tests different dosages to find the optimal amount. About 33% of Phase 2 drugs advance to Phase 3. If successful, the treatment will move to large-scale Phase 3 trials needed for FDA approval.

Why This Trial Matters

This trial aimed to address immunotherapy resistance in advanced cancers, particularly pancreatic cancer, by targeting a gene called RIPK1 that may help the immune system fight tumors. Phase 2 success would typically lead to larger Phase 3 trials needed for regulatory approval. This research targets Neoplasms, Pancreatic, where improved treatment options are needed.

Investor Insight

The trial was terminated early, indicating potential safety concerns or lack of efficacy, which significantly reduces its investment appeal and probability of approval. Phase 2 trials have approximately a 15-20% chance of eventually gaining FDA approval.

Is This Trial Right for Me?

Ask your doctor about the specific risks and potential side effects of GSK3145095 and pembrolizumab. Understand that participation required regular clinic visits for drug administration, blood tests, and tumor biopsies. Be aware that the trial was terminated, so the planned treatment and follow-up may not be completed as originally intended. The trial is being conducted at 6 sites. Always discuss clinical trial participation with your healthcare provider before making any decisions. This information is for educational purposes only and is not medical advice.

AI-generated analysis for educational purposes only. This is not medical advice. Discuss clinical trial participation with your doctor. Data sourced from ClinicalTrials.gov.

Study Design

• Study Type: INTERVENTIONAL
• Allocation: NON_RANDOMIZED
• Model: SEQUENTIAL
• Masking: NONE
• Enrollment: 8 participants

Interventions

• DRUG: GSK3145095 — GSK3145095 will be available as capsule (size 1 containing 5 to 25 mg GSK3145095 and size 0 containing 25 to 75 mg GSK3145095) or tablet (25, 50, 200 mg white to slightly covered round/oval shaped coated) for oral administration in the fasted stated with approximately 200 milliliters (mL) of water.
• DRUG: Pembrolizumab — Pembrolizumab will be available as solution for infusion (100 milligrams/ 4 milliliter) at a dose of 200 mg via IV infusion for 30 minutes (given the variability of infusion pumps from site to site, a window of -5 minutes and +10 minutes is permitted i.e., infusion time is 25 to 40 minutes).

Primary Outcomes

• Number of Participants With Non-serious Adverse Events (AEs) and Serious Adverse Events (SAEs)-Part 1 (Up to Day 95)
• Number of Participants With Non-serious AEs and SAEs-Part 2 (Up to 2 years and 90 days)
• Number of Participants With AEs by Severity Grades-Part 1 (Up to Day 95)
• Number of Participants With AEs by Severity Grades-Part 2 (Up to 2 years and 90 days)
• Number of Participants With Dose-limiting Toxicities (DLTs)-Part 1 (Up to Day 28)

Secondary Outcomes

• Best Overall Response (BOR) Rate-Part 1 (Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 95 days))
• Best Overall Response (BOR) Rate-Part 2 (Until response, disease progression, initiation of another anticancer therapy or death whichever is earlier (maximum follow-up up to 2 years and 90 days))
• Progression-free Survival (PFS)-Part 3 (Until disease progression or death whichever is earlier (maximum follow-up up to 2 years and 90 days))
• Progression-Free Survival (PFS) -Part 4 (Until disease progression or death whichever is earlier (maximum follow-up up to 2 years and 90 days))
• Overall Survival -Part 3 (Until death (maximum follow-up up to 2 years and 90 days))

Full Eligibility Criteria

Inclusion Criteria:

* Subjects must provide signed, written informed consent.
* Male and female subjects, age \>=18 years (at the time consent is obtained). a) Male subjects are eligible to participate if they agree to the following during the study treatment period and for at least 15 days (Part 1) and 120 days (Parts 2-4) after the last dose of study treatment: Refrain from donating sperm, be abstinent from heterosexual or homosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent or must agree to use contraception/barrier: male condom and female partner to use an additional highly effective contraceptive method with a failure rate of \<1 percent per year. b) female subjects are eligible to participate if they are not either pregnant or breastfeeding, and at least one of the following conditions applies: is not a woman of childbearing potential (WOCBP), is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of \<1 percent per year), with low user dependency during the study treatment period and for at least 15 days (Part 1) and 120 days (Parts 2-4) after the last dose of study treatment and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study treatment. Hormonal contraception may be susceptible to interaction with the study drug, which may reduce the efficacy of the contraceptive method. Therefore, a barrier method is also required for subjects using a hormonal option (including hormonal intrauterine device \[IUD\], oral contraceptive pills/ patch/ vaginal inserts, and hormonal implants) and both highly effective methods of contraception should be utilized during the treatment period and for at least 15 days (Part 1) and 120 days (Parts 2-4) after the last dose of study treatment.If a highly effective non-hormonal method is used, then only one method of contraception is required (by a female participant or partner of a male participant; in either situation the male partner must still use a male condom in addition) during the treatment period and for at least 15 days (Part 1) and 120 days (Parts 2-4) after the last dose of study treatment. A WOCBP must have a negative highly sensitive pregnancy test (urine or serum) as required by local regulations) within 24 hours before the first dose of study intervention. If a urine test cannot be confirmed as negative (e.g., 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. If the subject hasn't been on an acceptable method of contraception for at least 2 weeks prior to start of therapy, pregnancy testing must be done weekly for the first month of treatment. Additional requirements for pregnancy testing during and after study treatment. 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.
* Histological documentation of locally advanced, recurrent or PDAC (Part 1), non-small cell lung cancer (NSCLC), triple negative breast cancer (TNBC), or melanoma (Part 2) that has progressed after standard therapy appropriate for the specific tumor type, or for which standard therapy has proven to be ineffective, intolerable, or is considered inappropriate. Subjects should have received at least one, but not more than 2 prior lines of therapy for advanced disease including both standards of care and investigational therapies. Subjects whose cancers harbor molecular alterations for which targeted therapy is standard of care should have received health authority-approved appropriate targeted therapy for their tumor types before enrollment.
* All subjects in Parts 1 and 2 must consent to provide a fresh biopsy during screening of a primary tumor lesion or from other metastases (e.g. liver, lung, etc.), and a second biopsy after approximately 5 weeks of treatment.
* Measurable disease per RECIST version 1.1. Palpable lesions that are not measurable by radiologic or photographic evaluations may not be utilized as the only measurable lesion. Subjects are encouraged to provide a pre-Baseline scan (within 24 weeks before the Baseline scan) to support exploratory investigation of tumor growth kinetics.
* Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0 to 1.
* Life expectancy of at least 12 weeks.
* Adequate organ function.
* QT duration corrected for heart rate by Fridericia's formula (QTcF) \<450 milliseconds (or QTcF \<480 milliseconds for subjects with bundle branch block).

Exclusion Criteria:

* Prior treatment with the following agents: Agents affecting tumor associated macrophage function or number, including but not limited to inhibitors of R

Trial Locations

• GSK Investigational Site, Indianapolis, Indiana, United States
• GSK Investigational Site, New York, New York, United States
• GSK Investigational Site, New York, New York, United States
• GSK Investigational Site, New York, New York, United States
• GSK Investigational Site, Philadelphia, Pennsylvania, United States
• GSK Investigational Site, Houston, Texas, United States

Frequently Asked Questions

Related Conditions

• Pancreatic Neoplasms
• Neoplasms
• Solid Tumors
• Advanced Solid Tumors
• Metastatic Carcinoma
• Carcinoma
• Malignant Neoplasms
• Non-Small Cell Lung Cancer
• Triple Negative Breast Cancer
• Melanoma

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