Safety, Pharmacokinetics (PK) of AKT and MEK Combination

NCT01138085 | Completed Phase 1

• 1 other identifier: 113886
• Study Type: interventional
• Target: 240
• Locations: 1 country
• Sites: 10

Brief Summary

This study is a Phase 1 dose-escalation open-label study to determine the recommended Phase II dose (RP2D) and regimen for the combination of the orally administered MEK inhibitor GSK1120212 and the orally administered AKT kinase inhibitor GSK2141795. The study consists of two parts. Part 1A will identify the maximum tolerated dose (MTD) using a Zone-Based, modified 3 plus 3 dose escalation procedure. The starting dose (Zone 1, Cohort 1) will be 0.5mg GSK1120212 combined with 25mg GSK2141795. Dose escalation will continue based on predefined parameters until a MTD is established. The initial regimen for dose escalation in Part 1A will be continuous oral daily dosing. Once the continuous daily dosing MTD or RP2D has been established in Part 1A, Part 1B will explore alternate dosing schedule(s) in which the dosing schedule may be adjusted for either GSK1120212 or GSK2141795. Dose escalation will proceed using a 3 plus 3 dose escalation procedure until an MTD or RP2D of that alternate schedule is defined. Part 2 will explore further in specific tumor types the safety, tolerability, clinical activity, pharmacokinetic (PK) and pharmacodynamic (PD) properties of the combination of GSK1120212 and GSK2141795 at the recommended dose(s) and regimen(s) identified in Part 1.

Conditions

Cancer

Keywords

Triple negative breast cancer; BRAF wild-type melanoma; Solid tumors; Endometrial Cancer; Oncology; GSK2141795; AKT Inhibitor; GSK1120212

Outcome Measures

Primary Outcomes (3)

• Part 1A: To determine the safety, tolerability and recommended Phase II dose of GSK1120212 and GSK2141795 administered in combination orally, once daily continuously

  Duration of study.

• Part 1B:To determine the safety, tolerability and recommended Phase II dose of GSK1120212 and GSK2141795 administered in combination with an alternate schedule (i.e., at least one agent is dosed intermittently)

  Duration of study

• Parts 2A/2B: To evaluate the clinical activity of GSK1120212 and GSK2141795 administered in combination in subjects with solid tumors that are predicted to be sensitive to the inhibition of MEK and/or AKT, including TNBC and BRAF-wild type melanoma

  Duration of study

Secondary Outcomes (5)

• To characterize the PK of GSK1120212 and GSK2141795 for a once daily continuous dosing schedule (Part 1A) and/or an intermittent dosing schedule (Part 1B).

  duration of study

• Part 1A, Part 1B: To evaluate the clinical activity of GSK1120212 and GSK2141795 in subjects with solid tumors.

  Duration of study

• Parts 1 and 2: To characterize the durability of response with GSK1120212 and GSK2141795 dosed orally in combination

  Duration of study

• To evaluate the pharmacodynamic (PD) response in tumors after treatment with the combination of GSK1120212 and GSK2141795.

  Duration of study

• To explore relationships between study drug PK, PD and clinical activity

  Duration of study

Study Arms (2)

Dose Escalation

EXPERIMENTAL

Dose escalation will proceed until unacceptable toxicity is observed. Dose escalation decisions will take into account all available data, including PK data and the safety profile of prior cohorts and will occur following review of these data by the investigator(s), GSK medical monitor, pharmacokineticist, and statistician.

Drug: GSK1120212; Drug: GSK2141795

Expansion Cohorts

EXPERIMENTAL

Enrollment into expansion cohort(s) in Part 2A may begin once a recommended dosing regimen(s) is identified in Part 1A utilizing a once daily continuous dosing schedule for both GSK1120212 and GSK2141795. Enrolment to cohorts utilizing this daily dosing schedule may proceed in parallel with enrolment in Part 1B. Expansion cohort(s) will preferentially enroll subjects with treatment-refractory, measurable and biopsiable triple negative breast cancer or BRAF- wild type melanoma. Subjects selected for enrollment into Part 2A or Part 2B will be tested for PTEN deficiency and must agree to provide paired tumor biopsies (at baseline and once while on- treatment). An additional tumor biopsy at the time of disease progression should also be collected if feasible. In Part 2A and Part 2B, up to 35 additional subjects per tumor type and schedule (i.e., a total of up to 70 subjects per schedule tested) may be enrolled in a two-stage design to better characterize safety, PK and PD.

Drug: GSK1120212; Drug: GSK2141795

Interventions

GSK1120212 DRUG

MEK inhibitor

Dose Escalation; Expansion Cohorts

GSK2141795 DRUG

AKT Inhibitor

Dose Escalation; Expansion Cohorts

Eligibility Criteria

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

You may qualify if:

• Part 1 - Dose Escalation
• Subjects eligible for enrollment in the study must meet all of the following criteria:
• Male or female 18 years or older, at the time of signing the informed consent.
• Capable of giving written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
• Histologically or cytologically-confirmed diagnosis of solid tumor malignancy that is not responsive to standard therapies or for which there is no approved or curative therapy or for subjects who refuse standard therapy (Part 1A). Part 1B subjects must have a confirmed diagnosis of one of the following (documented lab results confirming mutational status must be available at Screening):
• colorectal cancer (CRC): KRAS mutation non-small cell lung (NSCLC): KRAS mutation Pancreatic: no mutational status specified Endometrial: no mutational status specified Ovarian: no mutational status specified Squamous cell carcinoma of the head and neck: no mutational status specified BRAF wild type melanoma (preferentially enrolled to Part 2) BRAF inhibitor failure melanoma. This includes BRAF-mutant melanoma that is either initially refractory to BRAF-inhibitor therapy OR that Initially responds to BRAF-inhibitor therapy but eventually develops documented radiographic progression to a BRAF inhibitor while on therapy Triple negative breast cancer (TNBC) (preferentially enrolled to Part 2) NOTE: Subjects who do not meet one of the categories described above but who have molecular evidence suggesting benefit from the study drugs may be considered for enrollment after discussion with the GlaxoSmithKline (GSK) Medical Monitor.
• Performance Status score of 0 or 1 according to the Eastern Cooperative Oncology Group (ECOG) scale.
• Able to swallow and retain oral medication.
• Must agree to collection of blood samples for the evaluation of circulating free DNA (cfDNA) (Part 1B or Part 2).
• A female subject is eligible to participate if she is of:
• Non-childbearing potential defined as pre-menopausal females with a documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous follicle stimulating hormone \[FSH\] greater than 40 MlU/ml and estradiol less than 40 pg/ml \[less than 140 pmol/L\] is confirmatory). Females on hormone replacement therapy \[HRT\] and whose menopausal status is in doubt will be required to use one of the contraception methods in Section 8.1.1 if they wish to continue their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation of post-menopausal status prior to study enrollment. For most forms of HRT, at least 2 to 4 weeks will elapse between the cessation of therapy and the blood draw; this interval depends on the type and dosage of HRT. Following confirmation of their post-menopausal status, they can resume use of HRT during the study without use of a contraceptive method.
• Child-bearing potential and agrees to use one of the contraception methods listed in Section 7.3.2 for an appropriate period of time (as determined by the product label or investigator) prior to the start of dosing to sufficiently minimize the risk of pregnancy at that point. Additionally, women of child-bearing potential must have a negative serum pregnancy test within 14 days prior to the first dose of study medication. Female subjects must agree to use contraception until four weeks after the last dose of study medication.
• Note: Oral contraceptives are not reliable due to potential drug-drug interaction and should only be used in combination with the alternative methods outlined in Section 8.1.1.
• Male subjects must agree to use one of the contraception methods listed in Section 8.1.2. This criterion must be followed from the time of the first dose of study medication until four months after the last dose of study medication.
• Adequate organ system function as defined in protocol. Absolute neutrophil count (ANC) greater than or equal to 1.5 X 10 to the ninth/L Hemoglobin greater than or equal to 9.5 g/dL Platelets greater than or equal to 75 X 10 to the ninth/L Prothrombin time (PT) / International Normalized Ratio (INR) and Partial Thromboplastin Time (PTT) less than or equal to 1.1 X ULN Total bilirubin less than or equal to 1.5 x ULN (isolated bilirubin greater than 1.5 x ULN is acceptable if bilirubin is fractionated and direct bilirubin less than 35 percent) AST and ALT less than or equal to 1.5 X ULN Albumin greater than 2.5 g/dL Creatinine less than or equal to ULN OR Calculated creatinine clearance greater than or equal to 30 mL/min OR 24-hour urine creatinine clearance greater than or equal to 30 mL/min

You may not qualify if:

• Subjects meeting any of the following criteria must not be enrolled in the study:
• Chemotherapy, radiotherapy, immunotherapy, or other anti-cancer therapy including investigational drugs within 28 days or 5 half lives, whichever is shorter prior to the first dose of any one of the investigational drugs described in this study. Prior exposure to either a MEK inhibitor or an AKT inhibitor is not permitted.
• Current use of a prohibited medication or requires any of these medications during treatment with the study treatments.
• Unresolved toxicity greater than National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE), version 4.0 (NCI-CTCAE v4) Grade 1 from previous anti-cancer therapy unless agreed to by a GSK Medical Monitor and the Investigator, and where a GSK Medical Monitor and the investigator consider that the ongoing toxicity will not introduce additional risk factors and will not interfere with the study procedures.
• Presence of active gastrointestinal (GI) disease or other condition that could affect gastrointestinal absorption (e.g. malabsorption syndrome) or predispose a subject to GI ulceration. Subjects with prior Whipple procedure are eligible.
• Evidence of mucosal or internal bleeding.
• Any major surgery within the last four weeks.
• Previously diagnosed with Type 1 diabetes mellitus.
• Previously diagnosed with Type 2 diabetes (Part 1A or Part 1B ONLY). Subjects with a history of steroid-induced hyperglycemia may be enrolled.
• Any malignancy related to human immunodeficiency virus (HIV), history of 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 (HCV) antibody.
• Known active infection requiring parenteral or oral anti-infective treatment.
• Subjects with leptomeningeal disease.
• Subjects with brain metastases are excluded if their brain metastases are:
• Symptomatic Treated (e.g., surgery, radiation therapy) but not clinically and radiographically stable one month after therapy (as assessed by at least two distinct contrast enhanced magnetic resonance imaging (MRI) or computerized axial tomography (CT) scans over at least a one month period), OR Asymptomatic and untreated but greater than 1 cm in the longest dimension Subjects with small (less than or equal to 1 cm in the longest dimension), asymptomatic brain metastases that do not need immediate therapy can be enrolled. Subjects must also be off of enzyme-inducing anticonvulsants for more than 4 weeks.
• Part 1B: Subjects with brain metastases who have been off corticosteroids for at least 2 months can be enrolled.

Sponsors & Collaborators

• GlaxoSmithKline: lead

Study Sites (10)

GSK Investigational Site

Aurora, Colorado, 80045, United States

Location

GSK Investigational Site

New Haven, Connecticut, 06520, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02114, United States

Location

GSK Investigational Site

Boston, Massachusetts, 02215, United States

Location

GSK Investigational Site

New Brunswick, New Jersey, 08901, United States

Location

GSK Investigational Site

Nashville, Tennessee, 37232, United States

Location

GSK Investigational Site

Dallas, Texas, 75246, United States

Location

GSK Investigational Site

Houston, Texas, 77230-1439, United States

Location

GSK Investigational Site

San Antonio, Texas, 78229, United States

Location

GSK Investigational Site

Salt Lake City, Utah, 84112-5550, United States

Location

Related Links

• Results for study 113886 can be found on the GSK Clinical Study Register.

MeSH Terms

Conditions

Neoplasms; Triple Negative Breast Neoplasms; Endometrial Neoplasms

Interventions

trametinib; GSK2141795

Condition Hierarchy (Ancestors)

Breast Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Uterine Neoplasms; Genital Neoplasms, Female; Urogenital Neoplasms; Uterine Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Diseases

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: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 22, 2010
• First Posted: June 7, 2010
• Study Start: May 4, 2010
• Primary Completion: November 19, 2014
• Study Completion: November 19, 2014
• Last Updated: November 13, 2017

Record last verified: 2017-11

Locations

US (10)