Clinical trial NCT01928940: Japan PhI/II of GSK2118436 and GSK1120212 Combination in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) or Cutaneous Melanoma (Phase II Part)
Official title: A Japanese Open-label Phase I/II Study to Assess the Safety, Tolerability, Pharmacokinetics and Efficacy of GSK2118436 and GSK1120212 Combination Therapy in Subjects With BRAF V600E/K Mutation Positive Advanced Solid Tumors (Phase I Part) and BRAF V600E/K Mutation Positive Cutaneous Melanoma (Phase II Part).
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Solid Tumours
Keywords: Advanced solid tumors
BRAF
Melanoma
Lead sponsor: GlaxoSmithKline
Sponsor class: INDUSTRY
First posted: 2013-08-27
Enrollment: 12
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part).

Detailed description: This is a Japanese Phase I/II, open-label, non-controlled study to evaluate the safety, tolerability, pharmacokinetic profile, and efficacy of the combination of GSK2118436 and GSK1120212 in subjects with BRAF V600E/K mutation positive advanced solid tumors (Phase I part) and BRAF V600E/K mutation positive cutaneous melanoma (Phase II part). Phase I part is designed to primarily assess the safety and tolerability of GSK2118436 and GSK1120212 combination therapy in subjects with BRAF V600E/K mutation positive advanced solid tumors. Six evaluable subjects will be enrolled into Phase I part and receive the combination therapy of GSK2118436 (150 mg, twice daily) and GSK1120212 (2 mg, once daily). A decision for starting Phase II part will be made by careful review based on available safety, tolerability and pharmacokinetic data in Phase I part. Phase II part is designed to primarily evaluate ORR of the combination as first-line therapy in subjects with unresectable (Stage IIIC) or metastatic (Stage IV) BRAF V600E/K mutation positive cutaneous melanoma. Subjects who have had prior systemic anti-cancer treatment in the advanced or metastatic setting will not be eligible for Phase II part although prior systemic treatment in the adjuvant setting will be allowed. Six evaluable subjects will be enrolled in Phase II part.

Eligibility criteria: Inclusion Criteria:

* Capable of given written informed consent, which includes compliance with the requirements and restrictions listed in the consent form.
* Male or female age 20 years or greater; able to swallow and retain oral medication.
* BRAF mutation positive advanced solid tumor ( Phase I part). BRAF mutation positive melanoma (Phase II part).
* Measurable disease according to RECIST version 1.1.
* Eastern Cooperative Oncology Group Performance Status of 0 or 1
* Agree to contraception requirements.
* Adequate organ system function.

Exclusion Criteria:

* Currently receiving cancer therapy (chemotherapy, radiation therapy, immunotherapy, or biologic therapy).
* Phase II part ONLY: Prior systemic anti-cancer treatment (chemotherapy, immunotherapy, biologic therapy, vaccine therapy, or investigational treatment) for Stage IIIC (unresectable) or Stage IV (metastatic) melanoma. Prior systemic treatment in the adjuvant setting is allowed.
* Any major surgery, extensive radiotherapy, chemotherapy with delayed toxicity, biologic therapy, or immunotherapy within 28 days prior to the study treatment (6 weeks for prior nitrosourea or mitomycin C), or daily or weekly chemotherapy without the potential for delayed toxicity within 14 days prior to the study treatment. Limited radiotherapy within the last 2 weeks. (Note: Ipilimumab treatment must end at least 8 weeks prior to the study treatment.)
* Taken an investigational drug within 28 days or 5 half-lives (minimum 14 days), whichever is shorter, prior to the study treatment.
* Current use of a prohibited medication or requires any of these medications during treatment with the study drugs.
* A history of another malignancy. Subjects who have been disease-free for 5 years, or subjects with a history of completely resected non-melanoma skin cancer, or successfully treated in situ carcinoma are eligible.
* Any serious or unstable pre-existing medical conditions (aside from malignancy exceptions specified above), psychiatric disorders, or other conditions that could interfere with the subject's safety, obtaining informed consent, or compliance with study procedures (e.g., uncontrolled diabetes).
* Presence of active gastrointestinal disease or other condition that will interfere significantly with the absorption, distribution, metabolism, or excretion of drugs.
* History of pneumonitis or interstitial lung disease.
* Known HIV infection.
* Certain cardiac abnormality
* A history or current evidence/risk of retinal vein occlusion or central serous retinopathy.
* Pregnant or lactating female.

Primary outcomes:
measure: Phase I: Number of Participants With Any Adverse Event (AE) and Any Serious Adverse Event (SAE)
timeFrame: From the start of study treatment until 30 days after study treatment discontinuation (average of 1.38 year)
measure: Phase I: Number of Participants With a Dose-limiting Toxicity (DLT)
timeFrame: From the start of study treatment until 21 days
measure: Phase I: Number of Participants With the Indicated Worst-case Change From Baseline (BL) in the Indicated Clinical Chemistry Parameters (CCPs)
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 year)
measure: Phase I: Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Hematology Parameters
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 year)
measure: Phase I: Number of Participants With the Indicated Urinalysis Parameters
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 year)
measure: Phase I: Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in Eastern Cooperative Oncology Group (ECOG) Performance (Pef) Status
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 year)
measure: Phase I: Number of Participants With Worst-case On-therapy Increase From Baseline in Systolic and Diastolic Blood Pressure to Grade 2 or Grade 3
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 year)
measure: Phase I: Number of Participants With Worst-case On-therapy Change From Baseline in Heart Rate
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 year)
measure: Phase I: Number of Participants With Worst-case On-therapy Change From Baseline in Temperature
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
measure: Phase I: Change From Baseline in Oxygen Saturation (SpO2) Measured Via Pulse Oxymetry at the Indicated Time Points
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 year)
measure: Phase I: Change From Baseline in Weight at the Indicated Time Points
timeFrame: From Baseline until the post-treatment Visit ( average of 1.38 year)
measure: Phase I: Number of Participants With the Indicated Electrocardiogram (ECG) Findings at the Indicated Time Points
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 year)
measure: Phase I: Number of Participants With Worst-case On-therapy Change From Baseline in Left Ventricular Ejection Fraction (LVEF) as Assessed by Echocardiogram (ECHO)
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
measure: Phase II: Number of Participant With Confirmed Overall Response
timeFrame: Every 8 weeks from start of the treatment until disease progression, death, or withdrawal of consent (average of 1.38 years)
Secondary outcomes:
measure: Phase I: Area Under the Plasma Concentration Versus Time Curve (AUC) of GSK2118436 and Metabolites, and GSK1120212 After Single and Repeat Dose
timeFrame: At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr on Day 21 (repeat dose)
measure: Phase I: Maximum Plasma Concentration (Cmax) of GSK2118436 and Metabolites, and GSK1120212 After a Single and Repeat Dose
timeFrame: At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr on Day 21 (repeat dose)
measure: Phase I: Plasma Trough Concentration (Ctau) of GSK2118436 and Metabolites, and GSK1120212 After a Single and Repeat Dose
timeFrame: At pre-dose on Day 8, Day 15, Weeks 3, 8, 16 and 24
measure: Phase I: Time of Occurrence of Cmax (Tmax) and Terminal Phase Half Life (t1/2) of GSK2118436 and Metabolites, and GSK1120212 After a Single and Repeat Dose
timeFrame: At pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10, 12 and 24 hr after administration of GSK2118436 + GSK1120212 on Day 1 (single dose) and at pre-dose, 0.5, 1, 1.5, 2, 3, 4, 6, 8, 10 and 12 hr on Day 21 (repeat dose)
measure: Phase I: Number of Participants With Confirmed Overall Response Rate
timeFrame: Every 8 weeks from start of the treatment until disease progression, death, or withdrawal of consent (average of 1.38 years)
measure: Phase I: Number of Participants With Unconfirmed Overall Response Rate
timeFrame: Every 8 weeks from start of the treatment until disease progression, death, or withdrawal of consent (average of 1.38 years)
measure: Phase I: Progression Free Survival (PFS)
timeFrame: From start of the treatment until disease progression or death (average of 1.38 years)
measure: Phase I: Duration of Response
timeFrame: From start of the treatment until disease progression or death (average of 1.38 years)
measure: Phase II: Number of Participants With Unconfirmed Overall Response
timeFrame: Every 8 weeks from start of the treatment until disease progression, death, or withdrawal of consent (average of 1.38 years)
measure: Phase II: Progression Free Survival (PFS)
timeFrame: From start of the treatment until disease progression or death (average of 1.38 years)
measure: Phase II: Duration of Response
timeFrame: From start of the treatment until disease progression or death (average of 1.38 years)
measure: Phase II: Number of Participants With Any Adverse Event and Any Serious Adverse Event
timeFrame: From the start of study treatment until 30 days after study treatment discontinuation (average of 1.38 years)
measure: Phase II: Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Clinical Chemistry Parameters
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
measure: Phase II: Number of Participants With the Indicated Worst-case Change From Baseline in the Indicated Hematology Parameters
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
measure: Phase II: Number of Participants With the Indicated Urinalysis Results
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
measure: Phase II: Number of Participants With the Indicated Worst-case On-therapy Change From Baseline in ECOG Perormance Status
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
measure: Phase II: Number of Participants With Worst-case On-therapy Increase From Baseline in Systolic and Diastolic Blood Pressure to Grade 2 or Grade 3
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
measure: Phase II: Number of Participants With Worst-case On-therapy Change From Baseline in Heart Rate
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
measure: Phase II: Number of Participants With Worst-case On-therapy Change From Baseline in Temperature
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
measure: Phase II: Change From Baseline in Oxygen Saturation Measured Via Pulse Oxymetry at the Indicated Time Points
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
measure: Phase II: Change From Baseline in Weight at the Indicated Time Points
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
measure: Phase II: Number of Participants With the Indicated Electrocardiogram Findings at the Indicated Time Points
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
measure: Phase II: Number of Participants With Worst-case On-therapy Change From Baseline in Left Ventricular Ejection Fraction as Assessed by Echocardiogram
timeFrame: From Baseline until the post-treatment Visit (average of 1.38 years)
Other outcomes:
Locations:
city: Shizuoka
country: Japan
facility: GSK Investigational Site
city: Tokyo
country: Japan
facility: GSK Investigational Site
Study officials:
affiliation: GlaxoSmithKline
name: GSK Clinical Trials
role: STUDY_DIRECTOR
References: