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A Phase I/IIa, First Time in Human, Open-label Dose-escalation Study of GSK2636771 in Subjects With Advanced Solid Tumors With PTEN Deficiency


Phase 1
18 Years
N/A
Open (Enrolling)
Both
Cancer

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Trial Information

A Phase I/IIa, First Time in Human, Open-label Dose-escalation Study of GSK2636771 in Subjects With Advanced Solid Tumors With PTEN Deficiency


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.


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.

Type of Study:

Interventional

Study Design:

Allocation: Non-Randomized, Endpoint Classification: Safety Study, Intervention Model: Single Group Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

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.

Outcome Description:

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)

Outcome Time Frame:

Single Dose Day 1 though 4

Safety Issue:

No

Principal Investigator

GSK Clinical Trials

Investigator Role:

Study Director

Investigator Affiliation:

GlaxoSmithKline

Authority:

United Kingdom: Medicines and Healthcare Products Regulatory Agency

Study ID:

115717

NCT ID:

NCT01458067

Start Date:

November 2011

Completion Date:

May 2013

Related Keywords:

  • Cancer

Name

Location

GSK Investigational SiteGermantown, Tennessee  38138
GSK Investigational SiteHartford, Connecticut  06106
GSK Investigational SiteSalt Lake City, Utah  84107