GSK2636771 + Pembrolizumab for Metastatic Melanoma

Age: 18+

Sex: Any

Trial Phase: Phase 1 & 2

Sponsor: M.D. Anderson Cancer Center

Must not be taking: Immunosuppressants, Steroids

Disqualifiers: Autoimmune disease, Active infections, Cardiovascular risk, others

No Placebo Group All trial participants will receive the active study treatment (no placebo)

Compensation: Varies

Number of Visits: 8

What You Need to Know Before You Apply

What is the purpose of this trial?

This trial aims to determine if combining GSK2636771, an investigational drug, with pembrolizumab, an immunotherapy drug, can manage metastatic melanoma that hasn't responded to other treatments. Researchers also seek to confirm the safety of this drug combination. The trial involves gradually increasing the dose of GSK2636771 to find the most effective and tolerable level, while all participants receive a consistent dose of pembrolizumab. Individuals with metastatic melanoma, who haven't had success with previous treatments and have specific tumor characteristics, might be suitable for this study. As a Phase 1 and Phase 2 trial, this study focuses on understanding how the treatment works in people and measuring its effectiveness in an initial, smaller group.

Will I have to stop taking my current medications?

The trial protocol does not specify if you need to stop taking your current medications. However, you must not have received any chemotherapeutic, biological, investigational agent, or radiation therapy within 28 days before starting the study drugs. It's best to discuss your current medications with the study doctor.

Is there any evidence suggesting that this trial's treatments are likely to be safe?

Research is examining the safety and effectiveness of combining GSK2636771 with pembrolizumab for treating metastatic melanoma. The FDA has already approved pembrolizumab for several cancers, including melanoma, indicating its safe use in many patients.

GSK2636771 remains under investigation. Early studies aim to determine the optimal dose that patients can tolerate without serious side effects. These studies gradually increase the dose to assess patient tolerance.

So far, no serious side effects have been reported at the early doses in these studies. This suggests the treatment might be well-tolerated, but further research is necessary to confirm this. As with any study, researchers will closely monitor the treatment's safety and effects. ^{1 2 3 4 5}

Why are researchers excited about this trial's treatments?

Researchers are excited about combining GSK2636771 with Pembrolizumab for treating metastatic melanoma because it targets the disease in a novel way. Unlike standard treatments that often focus solely on boosting the immune system, GSK2636771 works by inhibiting a specific pathway (PI3K beta) involved in cancer cell growth and survival. When paired with Pembrolizumab, an immunotherapy that enhances the body's immune response against cancer cells, this combination may offer a more comprehensive attack on melanoma. This dual approach has the potential to be more effective than current options, providing new hope for patients.

What evidence suggests that the combination of GSK2636771 and pembrolizumab could be effective for metastatic melanoma?

Research has shown that pembrolizumab helps treat melanoma by enabling the immune system to find and attack cancer cells. Studies have found that checkpoint inhibitors like pembrolizumab can help 35-40% of patients with advanced melanoma live longer and manage their disease better. In this trial, participants will receive a combination of pembrolizumab and GSK2636771, a drug targeting a specific part of cancer cells called PI3K-beta. Early research suggests that blocking PI3K-beta might make cancer cells easier to attack, possibly boosting the effects of pembrolizumab. This combination aims to improve treatment results for patients whose cancer hasn't responded to standard treatments. ^{1 2 3 4 5}

Who Is on the Research Team?

Hussein A. Tawbi

Principal Investigator

M.D. Anderson Cancer Center

Are You a Good Fit for This Trial?

This trial is for adults with metastatic melanoma that hasn't improved after treatment, including PD-1 or PD-L1 therapy. Participants must have PTEN loss in their tumors, measurable disease, and a life expectancy of at least 12 weeks. They should be able to take oral medication and have good organ function. Women of childbearing potential and men with partners of childbearing potential must agree to use contraception.

Inclusion Criteria

Be willing and able to provide written informed consent for the trial

My blood counts, kidney, liver, and heart functions are within safe ranges for treatment.

My tumor shows PTEN loss.

Exclusion Criteria

I have a history of serious heart issues or my heart doesn’t pump well.

I have had pneumonitis treated with steroids or have it now.

You have a history of testing positive for HIV. Testing for HIV at the time of screening is not needed.

Timeline for a Trial Participant

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment Phase 1

Participants receive GSK2636771 at escalating doses in combination with pembrolizumab to determine the maximum-tolerated dose.

3 weeks per cycle, up to 2 years

Visits on Day 1 of each cycle with additional visits for PK testing in Cycle 1

Treatment Phase 2

Participants receive GSK2636771 at the highest tolerated dose from Phase 1 in combination with pembrolizumab.

3 weeks per cycle, up to 2 years

Visits on Day 1 of each cycle with additional visits for PK testing in Cycle 2

Follow-up

Participants are monitored for safety and effectiveness after treatment.

Up to 30 days after end of study dosing and every 6 weeks

Physical exams and routine tests every 6 weeks, imaging every 12 weeks

Treatment Beyond Progression

Participants may continue to receive the study drug if the disease appears to be getting worse but the drug is deemed beneficial.

What Are the Treatments Tested in This Trial?

Interventions

• GSK2636771
• Pembrolizumab

Trial Overview The study tests GSK2636771 combined with pembrolizumab on patients whose metastatic melanoma has not responded to previous treatments. Pembrolizumab is FDA-approved; GSK2636771 isn't and is used only for research now. The aim is to see if this drug combo can control the disease better than current options.

How Is the Trial Designed?

Group I: GSK2636771 + Pembrolizumab Experimental Treatment 2 Interventions

Phase I: Participants receive the lowest dose level of GSK2636771. Each new group receives a higher dose of GSK2636771 than the group before it, if no intolerable side effects were seen. This will continue until the highest tolerable dose of GSK2636771 is found. Participants receive the same dose level of Pembrolizumab. Phase II: Participants receive GSK2636771 at the highest dose that was tolerated in Phase 1. Participants receive the same dose level of Pembrolizumab.

Who Is Running the Clinical Trial?

M.D. Anderson Cancer Center

Lead Sponsor

Trials

3,107

Recruited

1,813,000+

GlaxoSmithKline

Industry Sponsor

Trials

4,834

Recruited

8,389,000+

Headquarters

London, UK

Known For

Vaccines & Medicines

Top Products

**Advair (salmeterol, fluticasone propionate)**, **Shingrix (shingles vaccine)**, **Augmentin (amoxicillin/clavulanate potassium)**, **Ventolin (salbutamol sulfate)

Dame Emma Walmsley

GlaxoSmithKline

Chief Executive Officer since 2017

MA in Classics and Modern Languages from Oxford University

Dr. Hal Barron

GlaxoSmithKline

Chief Medical Officer since 2018

MD from Harvard Medical School

National Cancer Institute (NCI)

Collaborator

Trials

14,080

Recruited

41,180,000+

National Institutes of Health (NIH)

Collaborator

Trials

2,896

Recruited

8,053,000+

Merck Sharp & Dohme LLC

Industry Sponsor

Trials

4,096

Recruited

5,232,000+

Chirfi Guindo

Merck Sharp & Dohme LLC

Chief Marketing Officer since 2022

Degree in Engineering from Ecole Centrale de Paris, MBA from New York University Stern School of Business

Robert M. Davis

Merck Sharp & Dohme LLC

Chief Executive Officer since 2021

JD from Northwestern University Pritzker School of Law, MBA from Northwestern University Kellogg Graduate School of Management, Bachelor's in Finance from Miami University

Published Research Related to This Trial

In a post hoc analysis of the KEYNOTE-006 study involving 555 patients with advanced melanoma, both ipilimumab and BRAF ± MEK inhibitors showed antitumor activity as subsequent therapies after pembrolizumab, with overall response rates (ORR) of 17.5% for ipilimumab and 30.5% for BRAF ± MEK inhibitors.

Patients who had not previously received BRAF ± MEK inhibitors showed a significantly higher ORR of 43.2% when treated with these agents after pembrolizumab, indicating that prior treatment status may influence the effectiveness of subsequent therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Antitumor activity of ipilimumab or BRAF ± MEK inhibition after pembrolizumab treatment in patients with advanced melanoma: analysis from KEYNOTE-006. Long, GV., Arance, A., Mortier, L., et al.[2022]

Pembrolizumab is a monoclonal antibody that effectively blocks the PD-1 receptor on T cells, enhancing their ability to attack cancer cells, particularly in melanoma patients.

In a Phase I study involving 411 patients, pembrolizumab demonstrated high durable response rates with minimal toxicity, indicating its potential as a safe and effective treatment option for melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab joins the anti-PD-1 armamentarium in the treatment of melanoma. Hersey, P., Gowrishankar, K.[2017]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating advanced melanoma, showing an overall response rate of 24% in a trial of 89 patients, with 86% of responses lasting at least 6 months.

While there are potential immune-mediated side effects, the benefits of prolonged tumor response durations were deemed to outweigh these risks, marking an improvement over existing treatments.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Accelerated Approval of Pembrolizumab for Second-Line Treatment of Metastatic Melanoma. Chuk, MK., Chang, JT., Theoret, MR., et al.[2021]

The maximum tolerated doses (MTDs) for the combination of pembrolizumab and trametinib were established, with concurrent dosing showing a lower objective response rate (0%) compared to intermittent dosing (27%).

While the combination treatment had manageable safety profiles, with 31% of patients experiencing grade 3/4 treatment-related adverse events in the concurrent group, the overall antitumor activity was limited, suggesting that this combination may not be highly effective for solid tumors and BRAF wild-type melanoma.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

KEYNOTE-022: Pembrolizumab with trametinib in patients with BRAF wild-type melanoma or advanced solid tumours irrespective of BRAF mutation. Maio, M., Carlino, MS., Joshua, AM., et al.[2022]

Pembrolizumab (KEYTRUDA) was approved by the FDA for treating unresectable or metastatic melanoma based on two clinical trials involving 1,374 patients, showing significant improvements in overall survival compared to ipilimumab, with hazard ratios indicating a reduced risk of death.

Patients receiving pembrolizumab also experienced significant improvements in progression-free survival, although some immune-mediated adverse reactions like hypothyroidism and pneumonitis were noted, highlighting the importance of monitoring for side effects.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

FDA Approval Summary: Pembrolizumab for the Treatment of Patients with Unresectable or Metastatic Melanoma. Barone, A., Hazarika, M., Theoret, MR., et al.[2022]

In a phase II trial involving 15 patients with resectable non-small cell lung cancer (NSCLC), neoadjuvant treatment with pembrolizumab showed a major pathologic response in 27% of patients, indicating promising antitumor activity before surgery.

The treatment was found to be feasible and safe, with only 33% of patients experiencing moderate adverse events, and no postoperative mortality, suggesting that pembrolizumab does not compromise surgical outcomes.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Neoadjuvant anti-programmed death-1 immunotherapy by pembrolizumab in resectable non-small cell lung cancer: First clinical experience. Eichhorn, F., Klotz, LV., Kriegsmann, M., et al.[2022]

Pembrolizumab (Keytruda) is an effective treatment for advanced melanoma, showing significant improvements in progression-free survival and overall response rates compared to ipilimumab and chemotherapy in clinical trials involving patients with varying treatment histories.

The drug has a manageable safety profile, with immune-related side effects that are generally reversible, making it a valuable option for patients who have not responded to other therapies.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: A Review in Advanced Melanoma. Deeks, ED.[2022]

Pembrolizumab (Keytruda) is the first anti-PD-1 therapy approved in the US for treating advanced malignant melanoma, specifically for patients who have progressed after prior treatments.

It is designed to target the PD-1 protein, enhancing the immune system's ability to fight cancer, and is currently under review for approval in the EU.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab: first global approval. Poole, RM.[2021]

Pembrolizumab, a PD-1 inhibitor, has demonstrated clinical effectiveness in treating various solid tumors, particularly in patients with PD-L1-positive non-small-cell lung cancer and unresectable/metastatic melanoma.

Early-phase trials and ongoing studies are focused on further confirming the clinical benefits of pembrolizumab in thoracic malignancies, highlighting its potential as a significant treatment option in cancer therapy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab for the treatment of thoracic malignancies: current landscape and future directions. Karim, S., Leighl, N.[2017]

Pembrolizumab, an anti-PD-1 antibody, has shown significant efficacy in treating advanced melanoma, demonstrating superior progression-free survival compared to chemotherapy in Phase II trials and improved overall survival in Phase III trials.

The treatment is generally well tolerated with a favorable safety profile, though common side effects include fatigue and rash, while less frequent but serious immune-related adverse events can occur.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Pembrolizumab in the management of metastatic melanoma. Spain, L., Younger, E., Hatipoglu, E., et al.[2020]

Citations

1. clinicaltrials.gov clinicaltrials.gov/study/NCT03131908

NCT03131908 | Study of the Selective PI3K-Beta Inhibitor ... The goal of this clinical research study is to learn if GSK2636771 given in combination with pembrolizumab can help to control the disease in patients with ...

2. asco.org asco.org/abstracts-presentations/ABSTRACT316215

Safety results from phase I/II study of the PI3Kβ inhibitor ... Background: Checkpoint inhibitors (CPI) have improved survival and long-term disease control in 35-40% of pts with MM. Many pts derive no clinical benefit ...

3. pmc.ncbi.nlm.nih.gov pmc.ncbi.nlm.nih.gov/articles/PMC8724390/

The role of PI3'-lipid signalling in melanoma initiation ... A recent study evaluating the combination of the PI3Kβ inhibitor, GSK2636771, and pembrolizumab ... effective treatment of advanced melanoma. Front Biosci ...

4. mdanderson.org mdanderson.org/patients-family/diagnosis-treatment/clinical-trials/clinical-trials-index/clinical-trials-detail.ID2016-0774.html

Phase I/II Study of the selective PI3K-beta inhibitor ... The goal of this clinical research study is to learn if GSK2636771 given in combination with pembrolizumab can help to control the disease in patients with ...

5. cancer.gov cancer.gov/research/participate/clinical-trials-search/v?id=NCI-2018-01609

PI3K-beta Inhibitor GSK2636771 and Pembrolizumab in ... Giving PI3K-beta inhibitor GSK2636771 and pembrolizumab may work better in treating patients with metastatic cancer. Eligibility Criteria ...