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

NCT01458067 | Completed Phase 1

• 1 other identifier: 115717
• Study Type: interventional
• Target: 30
• Locations: 3 countries
• Sites: 8

Brief Summary

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. In Part 3, up to two tumor-specific expansion cohorts will be enrolled and receive the MTD or BED as defined in Part 2. A minimum of 12 and a maximum of 20 evaluable subjects will be enrolled in each cohort. Interim monitoring for futility will be incorporated after response data from 12 subjects are available. In addition, up to 20 evaluable subjects will be enrolled into Part 3 -Signal-finding Expansion Cohort at the MTD or BED as defined in Part 2. All subjects in all parts/cohorts will receive daily dosing until withdrawal or unacceptable toxicity. All subjects in all parts/cohorts will receive daily dosing until withdrawal or unacceptable toxicity.

Conditions

Cancer

Outcome Measures

Primary Outcomes (3)

• 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.

  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)

  Single Dose Day 1 though 4

• 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.

  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

  4 weeks

• Part 3 (Expansion cohorts):To further evaluate the clinical activity of oral GSK2636771 in PTEN deficient CRPC, CRC and multiple PTEN deficient tumor types.

  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

  Every 8 weeks

Secondary Outcomes (6)

• Part 1: characterize safety, tolerability, and pharmacokinetics following repeat-dose oral administration of GSK2636771.

  Through 2 years

• Part 2: evaluate the pharmacodynamic (PD) response in PTEN deficient tumors after treatment with GSK2636771.

  Through 2 years

• 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.

  Through 2 years

• Part 3: further characterize the PK of GSK2636771, given orally, following single- and repeat-dose administration.

  Through Day 23

• Part 3: further characterize the safety and tolerability of GSK2636771, given orally, following single- and repeat-dose administration.

  Through 2 years

Study Arms (3)

Part 1

EXPERIMENTAL

GSK2636771 single dose and then daily dosing after approximately 1 week

Drug: GSK2636771

Part 2

EXPERIMENTAL

GSK2636771 single dose and then daily dosing starting on Day 4

Drug: GSK2636771

Part 3

EXPERIMENTAL

GSK2636771 daily dosing

Drug: GSK2636771

Interventions

GSK2636771 DRUG

Oral capsules

Part 1; Part 2; Part 3

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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).
• Pre-screening Part 3 only
• Must have tumor amenable to biopsy Pre-screening Part 3 CRPC cohort only: prostate adenocarcinoma, surgically castrated or continuously medically castrated (for greater than or equal to 8 weeks prior to pre-screening), and
• persistent disease with evidence of disease progression following standard therapy(ies) including prior treatment with docetaxel and androgen/androgen receptor directed therapy, including enzalutamide and/or abiraterone
• serum testosterone level \<1.7 nmol/L or \<50 ng/dL
• PSA level of greater than or equal to 2.0 ng/mL For CRC cohort: CRC with persistent disease with evidence of disease progression following standard therapy(ies) that included multi-agent chemotherapy regimen(s) with exposure to oxaliplatin and irinotecan.
• For Signal-finding Expansion Cohort: one of the specified tumor types that is not responsive to standard therapies, or for which there is no approved or curative therapy, or for which subjects have refused standard therapy, including:
• Triple negative breast cancer (ER, PR, and HER2 negative), Endometriod, Gastric, Glioblastoma multiformae, Head/neck squamous cell carcinoma, Melanoma, Non-small cell lung cancer, Ovarian Screening Parts 1, 2 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.

You may not qualify if:

• 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 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

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (8)

GSK Investigational Site

New Haven, Connecticut, 06520, United States

Location

GSK Investigational Site

Oklahoma City, Oklahoma, 73104, United States

Location

GSK Investigational Site

Nashville, Tennessee, 37203, United States

Location

GSK Investigational Site

Salt Lake City, Utah, 84112, United States

Location

GSK Investigational Site

Seoul, 110-744, South Korea

Location

GSK Investigational Site

Seoul, 120/752, South Korea

Location

GSK Investigational Site

Sutton, Surrey, SM2 5PT, United Kingdom

Location

GSK Investigational Site

London, W1G 6AD, United Kingdom

Location

Related Links

• Results for study 115717 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Neoplasms

Interventions

GSK2636771

Study Officials

• GSK Clinical Trials

  GlaxoSmithKline

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 13, 2011
• First Posted: October 24, 2011
• Study Start: November 10, 2011
• Primary Completion: November 12, 2015
• Study Completion: February 25, 2016
• Last Updated: July 24, 2018

Record last verified: 2018-07

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF, CSR
• Time Frame: IPD is available via the Clinical Study Data Request site (click on the link provided below)
• Access Criteria: Access is provided after a research proposal is submitted and has received approval from the Independent Review Panel and after a Data Sharing Agreement is in place. Access is provided for an initial period of 12 months but an extension can be granted, when justified, for up to another 12 months.

Locations

GB (2); KR (2); US (4)