Phase I/IIa First Time in Human study of GSK2636771 in subjects with advanced solid tumors
Trial Purpose and Description
To be eligible for the main study, your tumor tissue must have a greatly reduced amount of the PTEN protein (that is, it must score negative for this protein by a test). The reduced level of this protein is thought to indicate who may benefit most from taking this drug. The results of the PTEN test of your tumor tissue must be available before you may be screened for the main part of the study. Until the results of the testing are available, screening for the main study will not begin. In Part 1, this study will look at how people react to, and how the body uses GSK2636771 at different amounts and at different times. The effects of the drug, both good and bad, will be studied. Information about how the study drug you get affects your body and your health will be collected through a number of tests and procedures. GSK2636771 has never been given to people before. It has only been tested in animals and in the laboratory. It is investigational because it is not approved by the FDA for doctors to prescribe to patients.
- 18 Years and older
A subject will be eligible for inclusion in this study only if all of the following criteria apply:
- 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;
- 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].
- 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).
- Able to swallow and retain orally administered medication.
- 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.
- 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
- 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
- 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 a PD expansion group (Part 2) must agree to undergo pre- and on-treatment tumor biopsies.
- 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:
- 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 (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.
- 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.
- Active peptic ulcer disease or history of abdominal fistula, GI perforation, or intra abdominal abscess within 28 days prior to beginning study treatment.
- History of congenital platelet function defect (e.g., Bernard-Soulier syndrome, Chediak-Higashi syndrome, Glanzmann thrombasthenia, storage pool defect).
- 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:
- 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 (NYHA, [NYHA, 1994]) functional classification system (Appendix 4).
- Baseline cardiac troponin (cTn I) >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.
- 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.
- February 2012
- Last Updated:
- Study HIC#:
Clinicaltrials.gov ID: Yale0327984