A Phase I/IIa, First Time in human, open-label dose-escalation study of GSK2636771 in subjects with advanced solid tumors with PTEN deficiency

Trial Purpose and Description

Trial Purpose

The study consists of a pre-screening period to determine if the subject’s tumor has phosphatase and tensin homolog (PTEN) deficiencies. Subjects then continue into the screening phase for Part 1, 2, or 3, as appropriate. In Part 1, 3 subjects will receive a single dose of 25 mg. After analysis of 24-hour pharmacokinetic (PK) samples, the subjects may receive continuous dosing or receive a single dose at another dose level.

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 the 72-hour PK sample. Additional subjects may be enrolled at lower dose levels for assessment of pharmacodynamics. 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 Stage 1 of Part 3, 12 subjects will be enrolled in each of three individual tumor-specific cohorts and receive the MTD or mBED determined in Part 2. If ≥1 of 12 subjects in Stage 1 of each cohort has a confirmed response by Response Evaluation Criteria In Solid Tumors 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.

Participation Guidelines

Eligibility Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:

1. 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;
2. 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 and Grade 2 anemia if hemoglobin ≥9.0 g/dL) at the time of treatment allocation [NCI-CTCAE, 2009].
3. Adequate organ system function as defined in Table 6. Performance Status score of 0 or 1 according to the ECOG scale (Section 8.2.6).
4. Able to swallow and retain orally administered medication.
5. 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 (see Section 11.1). Additionally, women of childbearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study medication.
6. 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
7. Glioblastoma multiformae (see additional details and criteria for GBM in Section 6.1.2)
   • Breast cancer (ER, PR, and HER2 negative)
   • Gastric adenocarcinoma
   • Colorectal cancer
   • Head/neck squamous cell carcinoma
   • Melanoma
8. 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.
9. Subjects enrolled as part of a PD expansion group (Part 2) must agree to undergo pre- and on-treatment tumor biopsies.
10. Subjects enrolled as part of the PK expansion group (Part 2) must agree to additional assessments, including duplicate PK samples, as well as collection of urine and bile samples.

A subject will not be eligible for inclusion in this study if any of the following criteria apply:

1. 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.
   
2. Current use of prohibited medication (see Section 10.2) 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 (see Table 6). Their use must be monitored in accordance with local institutional practice.
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. Please contact the GSK Medical Monitor if clarification is needed as to what GI abnormalities, conditions, or resections are exclusionary.
4. Active peptic ulcer disease or history of abdominal fistula, GI perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
5. History of congenital platelet function defect (e.g., Bernard-Soulier syndrome, Chediak-Higashi syndrome, Glanzmann thrombasthenia, storage pool defect).
6. Any major surgery within the last four weeks.
7. 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.
   
8. Known active infection requiring parenteral or oral anti-infective treatment.
9. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated respiratory, hepatic, renal or cardiac disease).
10. 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.
      
11. 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.
12. Other clinically significant ECG abnormalities including 2nd degree (Type II) or 3rd degree atrioventricular block.
13. History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty, or stenting or bypass grafting within the past 6 months.
14. Class III or IV heart failure as defined by the New York Heart Association (NYHA, [NYHA, 1994]) functional classification system (Appendix 4).
15. Baseline cardiac troponin (cTn I) >10% coefficient of variance (CV).
16. Known hypersensitivity to any of the components of the study treatment.
17. Pregnant or lactating female.
18. 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.
19. 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.

Sponsor:

GlaxoSmithKline

Dates:

February 2012

Last Updated:

Study HIC#:

1111009273

Clinicaltrials.gov ID: Yale0327984