What side effects are associated with this type of intervention?

Treatments for melanoma, particularly those involving immune checkpoint inhibitors like Pembrolizumab and targeted therapies such as PI3K-beta inhibitors, are associated with a range of side effects. Pembrolizumab can cause immune-related adverse events including skin reactions, endocrine issues, gastrointestinal problems, and serious conditions like pneumonitis and hepatitis. PI3K-beta inhibitors often lead to dermatitis, diarrhea, nausea, and peripheral edema. Combining these treatments may heighten the risk and severity of these adverse events.

What prior FDA approvals exist?

Pembrolizumab, a PD-1 inhibitor, has been FDA-approved for the treatment of several types of cancer, including melanoma. It is often used in combination with other agents to enhance its efficacy. For instance, the combination of pembrolizumab with ipilimumab, another immune checkpoint inhibitor, has shown clinical effectiveness in patients with advanced melanoma. While PI3K-beta inhibitors like GSK2636771 are still under investigation and not yet FDA-approved, the combination of such targeted therapies with pembrolizumab represents a promising area of research aimed at improving outcomes for patients with refractory metastatic melanoma.

What other types of research exist?

Promising alternatives for melanoma treatment in 2024 include: 1) Nivolumab plus Ipilimumab, which has shown improved progression-free survival in patients resistant to PD-1 inhibitors. 2) Talimogene laherparepvec (T-VEC) combined with Pembrolizumab, which has demonstrated efficacy in advanced melanoma. 3) Investigational agents like LAG-3 inhibitors (e.g., Relatlimab) combined with Nivolumab, which are showing promise in clinical trials.

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PI3K-Beta Inhibitor

GSK2636771 + Pembrolizumab for Metastatic Melanoma

Q: What is the mechanism of action of this treatment?

Melanoma treatments often target specific pathways to inhibit tumor growth and enhance the immune response. Pembrolizumab, a PD-1 inhibitor, works by blocking the PD-1 protein on T cells, preventing cancer cells from evading the immune system, thus allowing T cells to attack the tumor. GSK2636771, a PI3K-beta inhibitor, targets the PI3K pathway, which is involved in cell growth and survival, particularly in tumors with PTEN loss. By inhibiting this pathway, GSK2636771 can reduce tumor growth and proliferation. These mechanisms are crucial for melanoma patients as they offer targeted approaches to control and potentially reduce tumor burden, improving treatment outcomes.

Phase 1 & 2

Waitlist Available

Led By Hussein Tawbi, MD, PHD

Research Sponsored by M.D. Anderson Cancer Center

Eligibility Criteria Checklist

Specific guidelines that determine who can or cannot participate in a clinical trial

Must have

Be >/= 18 years of age on day of signing informed consent

Within 10 days of treatment initiation, the subject must demonstrate adequate organ function defined as follows: Absolute neutrophil count must be >/= 1500 per microliter (uL). Platelets must be >/=100,000 per uL. Hemoglobin must be >/= 9 grams per deciliter or >/= 5.6 millimoles per liter without transfusion or EPO dependency within 7 days of assessment. Serum creatinine must be </= 1.0 times the upper limit of normal (ULN) OR measured or calculated creatinine clearance per institutional standard (Glomerular Filtration Rate (GFR) can also be used in place of creatinine or CrCl) must be >/= 60 milliliters per minute OR proteinuria by urine dipstick must be </= 1+. Aspartate aminotransferase (AST) AND alanine aminotransferase (ALT) must be </= 2.5 times the ULN OR each must be </= 5 times the ULN for subjects with liver metastases. Alkaline phosphatase (ALP) must be </= 2 times the ULN. Serum total bilirubin must be </= 2.0 milligrams per deciliter except in patients with Gilbert's disease. Direct bilirubin must be </= the upper limit of normal for subjects with total bilirubin levels > 1.5 times the upper limit of normal. Albumin must be >/= 2.5 grams per deciliter. Left ventricular ejection fraction (LVEF) must be >/= 50% by echocardiogram (ECHO) or Multigated Acquisition (MUGA) scan. International Normalized Ratio (INR) must be </= 1.5 times the upper limit of normal unless the subject is receiving anticoagulant therapy as long as prothrombin time(PT) or partial thromboplastin time(PTT) is within therapeutic range of intended use of anticoagulants. Activated partial thromboplastin time(aPTT) must be </= 1.5 times the upper limit of normal unless the subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. Serum phosphate must be within normal limit. Serum calcium must be within normal limit

Must not have

History or evidence of cardiovascular risk including any of the following: - Clinically significant electrocardiogram (ECG) abnormalities including second degree (Type II) or third degree atrioventricular block - History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, stenting, or bypass grafting within the past 6 months prior to enrollment - Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system - Left ventricular ejection fraction (LVEF) below 50% - Known cardiac metastases

Has a history of (non-infectious) pneumonitis that required steroids or current pneumonitis

Timeline

Screening 3 weeks

Treatment Varies

Follow Up 2 years

Awards & highlights

No Placebo-Only Group

Summary

This trial tests a new drug (GSK2636771) combined with an existing treatment (pembrolizumab) for patients with melanoma that hasn't responded to other treatments. Pembrolizumab helps the immune system fight cancer, and GSK2636771 might enhance this effect.

Who is the study for?

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.

What is being tested?

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.

What are the potential side effects?

While specific side effects are not listed here, common ones associated with cancer therapies like pembrolizumab include fatigue, skin reactions, diarrhea, musculoskeletal pain, fever, coughing and shortness of breath among others. Side effects from GSK2636771 are unknown due to its experimental nature.

Eligibility Criteria

Inclusion Criteria

You may be eligible if you check “Yes” for the criteria below

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I am 18 years old or older.

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

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My tumor shows PTEN loss.

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I am fully active or restricted in physically strenuous activity but can do light work.

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I can take pills by mouth and keep them down.

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I haven't had any cancer treatment or used new medical devices in the last 28 days.

Exclusion Criteria

You may be eligible for the trial if you check “No” for criteria below:

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

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

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I am not using, nor will I need, any medication not allowed in the study. I understand the flu shot is okay, but nasal spray vaccines are not.

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I have an active tuberculosis infection.

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I do not have any serious infections or conditions like heart attack, stroke, or severe breathing problems.

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I have a significant stomach or intestine issue that affects food absorption.

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I do not have severe or uncontrolled health issues like heart, liver, kidney, or lung diseases.

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I have a genetic condition affecting my platelets.

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I am allergic to Pembrolizumab, GSK2636771, or their ingredients.

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I have not received a live vaccine in the last 30 days.

Timeline

Screening ~ 3 weeks3 visits

Treatment ~ Varies

Follow Up ~ 2 years

Screening ~ 3 weeks

Treatment ~ Varies

Follow Up ~2 years

This trial's timeline: 3 weeks for screening, Varies for treatment, and 2 years for reporting.

Treatment Details

Study Objectives

Study objectives can provide a clearer picture of what you can expect from a treatment.

Primary study objectives

Maximum-Tolerated Dose (MTD) of GSK2636771 in Combination with Pembrolizumab in Participants with Metastatic Melanoma and PTEN Loss

Objective Response Rate (ORR) of GSK2636771 in Combination with Pembrolizumab in Participants with Metastatic Melanoma and PTEN Loss

Secondary study objectives

Overall survival (OS)

Side effects data

From 2019 Phase 1 trial • 37 Patients • NCT02215096

55%

Diarrhoea

36%

Nausea

27%

Fatigue

27%

Anaemia

18%

Decreased appetite

18%

Hypocalcaemia

18%

Blood creatinine increased

18%

Blood alkaline phosphatase increased

18%

Dizziness

18%

Cough

18%

Hypophosphataemia

18%

Neutropenia

18%

Dysgeusia

18%

Haematuria

18%

Constipation

18%

Pain in extremity

18%

Hyperkalaemia

18%

Oropharyngeal pain

Malaise

Abdominal pain

Hypertension

Back pain

Hot flush

Blood phosphorus increased

Hypotension

Proteinuria

Urinary tract infection

Abdominal tenderness

Agitation

Cellulitis

Chills

Dyspepsia

Epistaxis

Face oedema

Fall

Hydronephrosis

Hyperglycaemia

Hypernatraemia

Hypersensitivity

Hypoalbuminaemia

Inguinal hernia

Insomnia

Mouth ulceration

Myalgia intercostal

Nasopharyngitis

Palpitations

Paraesthesia

Rash

Sinus bradycardia

Skin laceration

Arthralgia

Lymphocyte count decreased

Dry skin

Pelvic pain

Arthritis

Aspartate aminotransferase increased

Confusional state

Abdominal distension

Hyponatraemia

Pyrexia

Alopecia

Conjunctivitis

Gout

Peripheral swelling

Pollakiuria

100%

80%

60%

40%

20%

Study treatment Arm

GSK2636771 200mg/Enzalutamide 160mg Escalation

GSK2636771 400mg/Enzalutamide 160mg Escalation

Enzalutamide Only (run-in Period)

GSK2636771 200mg/Enzalutamide 160mg Expansion

GSK2636771 300mg/Enzalutamide 160mg Escalation

Awards & Highlights

No Placebo-Only Group

All patients enrolled in this study will receive some form of active treatment.

Trial Design

1Treatment groups

Experimental Treatment

Group I: GSK2636771 + PembrolizumabExperimental Treatment2 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.

Treatment

First Studied

Drug Approval Stage

How many patients have taken this drug

GSK-2636771

Not yet FDA approved

Pembrolizumab

FDA approved

0 / 16Eligibility criteria met

Research Highlights

Information in this section is not a recommendation. We encourage patients to speak with their healthcare team when evaluating any treatment decision.

Mechanism Of Action

Side Effect Profile

Prior Approvals

Other Research

Melanoma treatments often target specific pathways to inhibit tumor growth and enhance the immune response. Pembrolizumab, a PD-1 inhibitor, works by blocking the PD-1 protein on T cells, preventing cancer cells from evading the immune system, thus allowing T cells to attack the tumor. GSK2636771, a PI3K-beta inhibitor, targets the PI3K pathway, which is involved in cell growth and survival, particularly in tumors with PTEN loss. By inhibiting this pathway, GSK2636771 can reduce tumor growth and proliferation. These mechanisms are crucial for melanoma patients as they offer targeted approaches to control and potentially reduce tumor burden, improving treatment outcomes.