A Phase I/IIa, First Time in Human, Study of GSK2636771 in Subjects With Advanced Solid Tumors With Phosphatase and Tensin Homolog (PTEN) Deficiency

• Part 1 (Initial Dose Selection): characterize safety, tolerability, and pharmacokinetics following single dose oral administration of GSK2636771 and to determine the starting dose for Part 2. [ Time Frame: Single Dose Day 1 though 4 ] [ Designated as safety issue: No ]
  Pharmacokinetic parameters including AUC, Cmax, tmax, and t1/2; adverse events, serious adverse events, changes in laboratory values, ECG parameters, and vital signs; median and maximum AUC(0-24)
• Part 2 (Dose Escalation): characterize safety, tolerability, and pharmacokinetics following single- and repeat-dose oral administration of GSK2636771 and to determine the recommended dose and schedule for Part 3. [ Time Frame: 4 weeks ] [ Designated as safety issue: No ]
  Pharmacokinetic parameters including AUC, Cmax, tmax, and t1/2; adverse events, serious adverse events, changes in laboratory values, ECG parameters, and vital signs; dose-limiting toxicities and/or biological activity in tumor or anti-tumor efficacy
• Part 3 (Tumor-specific expansion cohorts): determine preliminary efficacy of GSK2636771 in the PTEN deficient subgroup of castrate-resistant prostate cancer, endometrial carcinoma, and gastric adenocarcinoma. [ Time Frame: Every 8 weeks ] [ Designated as safety issue: No ]
  Overall Response Rate (ORR): defined as the percentage of subjects with a confirmed complete response (CR) or partial response (PR) as per RECIST 1.1 criteria

• Part 1: characterize safety, tolerability, and pharmacokinetics following repeat-dose oral administration of GSK2636771. [ Time Frame: Through 2 years ] [ Designated as safety issue: No ]
  adverse events, serious adverse events, changes in laboratory values, ECG parameters, and vital signs
• Part 2: evaluate the pharmacodynamic (PD) response in PTEN deficient tumors after treatment with GSK2636771. [ Time Frame: Through 2 years ] [ Designated as safety issue: No ]
  change from baseline in PD biomarkers which may include: platelet function, pathway proteins in tumor biopsy specimens and surrogate tissue, and/or soluble or cellular markers found in blood; ORR, defined as the percentage of subjects with a confirmed CR or PR as per RECIST 1.1 criteria; Duration of Response: defined, for the subset of subjects with a confirmed CR or PR, as the time from first documented evidence of CR or PR until first documented disease progression or death due to any cause
• Part 3: further evaluate: the PD response in PTEN deficient tumors after treatment with GSK2636771; relationships between GSK2636771 PK, PD markers, and clinical endpoints; clinical tumor response after treatment with GSK2636771. [ Time Frame: Through 2 years ] [ Designated as safety issue: No ]
  change from baseline in PD biomarkers which may include: platelet function, pathway proteins in tumor biopsy specimens/surrogate tissue, and/or soluble or cellular markers found in blood; change from baseline in circulating tumor cells (CTC) concentration in prostate cancer subjects; CTC Response Rate: defined as the number of subjects going from >5 CTCs to <5 CTCs per 7.5ml of blood (prostate cancer subjects only); Duration of Response; Progression Free Survival: defined as interval between date of first dose and earliest date of disease progression or death due to any cause
• Part 3: further characterize the PK of GSK2636771, given orally, following single- and repeat-dose administration. [ Time Frame: Through Day 23 ] [ Designated as safety issue: No ]
  population pharmacokinetic parameters for GSK2636771 following single- and repeat-dose oral administration, including AUC and Vdss, and absorption rate constant (ka)
• Part 3: further characterize the safety and tolerability of GSK2636771, given orally, following single- and repeat-dose administration. [ Time Frame: Through 2 years ] [ Designated as safety issue: No ]
  adverse events and changes in laboratory values, ECG parameters, and vital signs following repeat-dose oral administration of GSK2636771
• Part 3: confirm the Part 3 dose as the recommended Phase II dose (RP2D). [ Time Frame: Through 2 years ] [ Designated as safety issue: No ]
  evaluation of all Part 3 measures

The study consists of a pre-screening period to determine if the subject's tumor has PTEN deficiencies. Subjects then continue into the screening phase for Part 1, 2, or 3, as appropriate. In Part 1, subjects will then receive a single dose of 25 mg. After analysis of 24 hour pharmacokinetic (PK) samples, subjects may receive continuous dosing or receive a single modified dose. In Part 2, subjects will be enrolled and dose escalation will occur in a 3+3 design. Subjects will receive a single dose on Day 1, and then begin continuous daily dosing after collection of a 72-hour PK sample. Additional subjects may be enrolled at lower dose levels for assessment of pharmacodynamic response. Once the maximum tolerated dose (MTD)/ maximum biologically effective dose (mBED) is determined, 12 subjects will be enrolled at that dose level and will have additional PK sampling, as well as urine and bile sampling for drug metabolite profiling. In Part 3, 12 subjects will be enrolled in Stage 1 of one of three individual tumor-specific cohorts and receive the MTD or mBED, as determined in Part 2. If >=1 of 12 subjects in each cohort has a confirmed response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, an additional 18 subjects will be enrolled in Stage 2. If not, the cohort will be closed. All subjects in all parts/cohorts will receive daily dosing until withdrawal or unacceptable toxicity.

The study consists of a pre-screening period to determine if the subject's tumor has PTEN deficiencies. Subjects then continue into the screening phase for Part 1, 2, or 3, as appropriate. In Part 1, subjects will then receive a single dose of 25 mg. After analysis of 24 hour pharmacokinetic (PK) samples, subjects may receive continuous dosing or receive a single modified dose. In Part 2, subjects will be enrolled and dose escalation will occur in a 3+3 design. Subjects will receive a single dose on Day 1, and then begin continuous daily dosing after collection of a 72-hour PK sample. Additional subjects may be enrolled at lower dose levels for assessment of pharmacodynamic response. Once the maximum tolerated dose (MTD)/ maximum biologically effective dose (mBED) is determined, 12 subjects will be enrolled at that dose level and will have additional PK sampling, as well as urine and bile sampling for drug metabolite profiling. In Part 3, 12 subjects will be enrolled in Stage 1 of one of three individual tumor-specific cohorts and receive the MTD or mBED, as determined in Part 2. If >=1 of 12 subjects in each cohort has a confirmed response by Response Evaluation Criteria In Solid Tumors (RECIST) 1.1, an additional 18 subjects will be enrolled in Stage 2. If not, the cohort will be closed. All subjects in all parts/cohorts will receive daily dosing until withdrawal or unacceptable toxicity.

• Experimental: Part 1
  GSK2636771 single dose and then daily dosing after approximately 1 week
  Intervention: Drug: GSK2636771
• Experimental: Part 2
  GSK2636771 single dose and then daily dosing starting on Day 4
  Intervention: Drug: GSK2636771
• Experimental: Part 3
  GSK2636771 daily dosing
  Intervention: Drug: GSK2636771

Inclusion Criteria:

Pre-screening Parts 1, 2, and 3

• Male or female at least 18 years of age at the time of signing the informed consent form and capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
• Able to swallow and retain orally administered medication.
• Sufficient archival tumor biopsy specimen is available for PTEN IHC analysis, or subject is willing to undergo a fresh tumor biopsy for PTEN IHC analysis.

Pre-screening Parts 1 and 2 only

• Histologically or cytologically confirmed diagnosis of one of the following solid tumor malignancies that is not responsive to standard therapies or for which there is no approved or curative therapy or for subjects that refuse standard therapy: Endometrial cancer (endometriod), Prostate cancer, Ovarian cancer, Non-small cell lung cancer, Breast cancer (ER, PR, and HER2 negative), Gastric adenocarcinoma, Colorectal cancer, Head/neck squamous cell carcinoma, Melanoma, or Glioblastoma multiformae at first or second recurrence (more specific disease history is detailed in the study protocol).

Screening Parts 1, 2, and 3 includes Pre-screening criteria (above) and

• For Parts 1 and 2, histologically or cytologically confirmed diagnosis of one of the following solid tumor malignancies that is not responsive to standard therapies or for which there is no approved or curative therapy or for subjects that refuse standard therapy: Endometrial cancer (endometriod), Prostate cancer, Ovarian cancer, Non-small cell lung cancer, Breast cancer (ER, PR, and HER2 negative), Gastric adenocarcinoma, Colorectal cancer, Head/neck squamous cell carcinoma, Melanoma, or Glioblastoma multiformae at first or second recurrence (more specific disease history is detailed in the study protocol). For Part 3, histologically or cytologically confirmed diagnosis of one of the following solid tumor malignancies that is not responsive to standard therapies or for which there is no approved or curative therapy or for subjects that refuse standard therapy: Endometrial cancer (endometriod), Prostate cancer, or Gastric adenocarcinoma.
• All prior treatment-related toxicities must be National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), Version 4.0, <=Grade 1 (except alopecia) at the time of treatment allocation with the exception of peripheral neuropathy, which must be <=Grade 2.
• Adequate organ system function defined as ANC greater than or equal to 1X10^9/L without growth factor in the past 7 days, hemoglobin greater than or equal to 9g/dL without transfusion in the past 7 days, platelets greater than or equal to 75X10^9/L without transfusion in the past 7 days, PT/INR and PTT less than or equal to 1.5XULN, total bilirubin less than or equal to 1.5XULN (isolated bilirubin >1.5XULN is acceptable if bilirubin is fractionated and direct bilirubin <35%), AST and ALT less than or equal to 2.5XULN (AST/ALT can be up to 4XULN in the presence of liver metastasis, but cannot be associated with elevated bilirubin), calculated creatinine clearance or 24-hour urine creatinine clearance greater than or equal to 50mL/min, cardiac ejection fraction greater than or equal to LLN by echocardiography.
• Women of childbearing potential and men with reproductive potential must be willing to practice acceptable methods of birth control prior to and after the start of dosing. Additionally, women of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study medication.
• Subjects must have tumors with a documented PTEN deficiency using an analytically validated IHC assay or other correlative assay (e.g., FISH). Determination of PTEN deficiency using archival tumor is acceptable. Where archival tissue is not available or does not confirm PTEN deficiency, a fresh tumor sample will be acceptable for screening, and those with PTEN deficiency will be eligible.
• Subjects enrolled as part of PD expansion group (Part 2) must agree to undergo pre- and on-treatment tumor biopsies.
• All subjects enrolled in Part 3 must agree to undergo pre- and on-treatment tumor biopsies until at least five evaluable biopsy pairs from each Part 3 cohort have been obtained.

Exclusion Criteria:

Pre-screening Parts 1, 2, and 3

• Presence of any clinically significant GI abnormalities or other condition that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels.
• History of congenital platelet function defect (e.g., Bernard-Soulier syndrome, Chediak-Higashi syndrome, Glanzmann thrombasthenia, storage pool defect)
• Any serious or unstable pre-existing medical, psychiatric, or other condition (including laboratory abnormalities) that could interfere with subject's safety or providing informed consent.

Screening Parts 1, 2, and 3 includes Pre-screening criteria (above) and

• Subject has had chemotherapy, radiotherapy, immunotherapy, or other anti-cancer therapy including investigational drugs within 14 days prior to the first dose of the investigational drug described in this study. Hormonal (e.g., anti-androgen) therapies for prostate cancer must be stopped 4 to 6 weeks prior to enrolment. NOTE: Subjects with prostate cancer may remain on LHRH agonists. Subjects with prostate cancer may remain on low-dose prednisone or prednisolone (up to 10 mg per day) and still be eligible for this study.
• Current use of prohibited medication during treatment with GSK2636771. Current use of aspirin, clopidogrel, ticlopidine, prasugrel, or ticagrelor is prohibited. Anticoagulants are permitted only if the subject meets PTT and INR entry criteria. Their use must be monitored in accordance with local institutional practice.
• Active peptic ulcer disease or history of abdominal fistula, GI perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
• Any major surgery within the last four weeks.
• Poorly controlled hypertension (defined as systolic blood pressure of >=150 mmHg or diastolic blood pressure of >100 mmHg based on a mean of 3 measurements at approximately 2-minute intervals). NOTE: Initiation or adjustment of antihypertensive medication(s) is permitted prior to study entry.
• Known active infection requiring parenteral or oral anti-infective treatment.
• Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal or cardiac disease).

• Subjects with brain metastases of non-central nervous system (CNS) primary tumors are excluded if their brain metastases are:

  • Symptomatic
  • Treated (surgery, radiation therapy) but not clinically and radiographically stable one month after local therapy (as assessed by contrast enhanced magnetic resonance imaging [MRI] or computed tomography [CT]), OR
  • Asymptomatic and untreated but >1 cm in the longest dimension
  • Subjects with small (<=1 cm in the longest dimension), asymptomatic brain metastases that do not need immediate local therapy can be enrolled.
  • NOTE: Subjects on a stable (i.e., unchanged) dose of corticosteroids for more than one month, or those who have been off corticosteroids for at least 2 weeks can be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for more than 4 weeks
• QTcF interval >=470 msecs. If a screening QTcF is >=470 msecs, it should be repeated 2 additional times at least 5 minutes apart and the average of the 3 readings should be used to determine eligibility.
• Other clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd degree atrioventricular block.
• History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within the past 6 months.
• Class III or IV heart failure as defined by the New York Heart Association functional classification system.
• Baseline cardiac troponin (cT-n) >10% coefficient of variance (CV).
• Known hypersensitivity to any of the components of the study treatment.
• Pregnant or lactating female.
• Any malignancy related to human immunodeficiency virus (HIV) or solid organ transplant; history of known HIV, history of known Hepatitis B virus (HBV) surface antigen positivity (subjects with documented laboratory evidence of HBV clearance may be enrolled) or positive Hepatitis C virus antibody confirmed by recombinant immunoblot assay.