A Combination Therapy Study of MK-2206 and AZD6244 in Participants With Advanced Solid Tumors (MK-2206-010)

Study Overview
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Brief Summary
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This study will investigate the safety and tolerability of combination therapy with MK-2206 and AZD6244 (selumetinib) and determine the maximum tolerated dose (MTD) and recommended Phase 2 dose (RPTD) for this drug combination in the treatment of participants with locally advanced or metastatic solid tumors. Preliminary efficacy data will also be collected. The primary hypotheses for this study are that: 1) the Dose-limiting Toxicities (DLTs) observed in participants with locally advanced or metastatic solid tumors after administration of combination therapy with MK-2206 and AZD6244 will be dose-dependent and allow for identification of the MTD, and 2) oral administration of combination therapy with MK-2206 and AZD6244 to participants with advanced solid tumors will be generally well-tolerated.

Official Title
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A Phase I Study of Oral MK-2206 in Combination With Oral AZD6244 in Patients With Locally Advanced or Metastatic Solid Tumors

Conditions
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Locally Advanced or Metastatic Solid Tumors

Intervention / Treatment
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* Drug: MK-2206
* Drug: AZD6244


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant has confirmed metastatic or locally advanced solid tumor that has failed to respond to standard therapy, progressed despite standard therapy, or therapies known to provide clinical benefit, or for whom efficacious standard therapy or any other therapy known to provide clinical benefit does not exist Participant has no history of prior cancer, except certain cervical, skin, or prostate cancers, or has undergone potentially curative therapy with no evidence of disease for 5 years At least 18 years of age Participant is able to swallow oral medications For participants enrolled in the MTD expansion cohorts, must have a diagnosis of Kirsten rat sarcoma viral oncogene homolog (KRAS) tumor-type non small-cell lung cancer (NSCLC). Additional tumor types (with specific mutations) may be added to the MTD expansion cohorts after discussion between Sponsor and Investigator Exclusion Criteria: Participant has had chemotherapy, radiotherapy or biological therapy within 4 weeks of entering the study Participant is currently participating in or has participated in a study of an investigational compound or device within 30 days or 5x the compound's half-life of Cycle 1, Day 1 Participant has known central nervous system metastases and/or carcinomatous meningitis Participant has a primary central nervous system tumor or spinal cord compression Participant is, at the time of signing informed consent, a regular user (including recreational use) of any illicit drugs or had a recent history (within the last year) of drug or alcohol abuse Participant is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study Participant is human immunodeficiency virus (HIV) positive Participant is has history of hepatitis B or C or active hepatitis A Participant has a history or current evidence of heart disease Participant has uncontrolled high blood pressure Participant has poorly controlled diabetes

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MK-2206 45 mg QOD + AZD6244 75 mg QD<br>Participants receive MK-2206 45 mg oral tablets once every other day (QOD) PLUS AZD6244 75 mg oral capsules once daily (QD) starting on Day 1 of each 28-day cycle. | Drug: MK-2206<br>* Oral tablets<br>Drug: AZD6244<br>* Oral capsules<br>* Other names: selumetinib;|
| Experimental: MK-2206 45 mg QOD + AZD6244 75 mg BID<br>Participants receive MK-2206 45 mg oral tablets QOD PLUS AZD6244 75 mg oral capsules twice daily (BID) starting on Day 1 of each 28-day cycle. | Drug: MK-2206<br>* Oral tablets<br>Drug: AZD6244<br>* Oral capsules<br>* Other names: selumetinib;|
| Experimental: MK-2206 90 mg QW + AZD6244 50 mg BID<br>Participants receive MK-2206 90 mg oral tablets once weekly (QW) PLUS AZD6244 50 mg oral capsules BID starting on Day 1 of each 28-day cycle. | Drug: MK-2206<br>* Oral tablets<br>Drug: AZD6244<br>* Oral capsules<br>* Other names: selumetinib;|
| Experimental: MK-2206 90 mg QW + AZD6244 75 mg QD<br>Participants receive MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules QD starting on Day 1 of each 28-day cycle. | Drug: MK-2206<br>* Oral tablets<br>Drug: AZD6244<br>* Oral capsules<br>* Other names: selumetinib;|
| Experimental: MK-2206 90 mg QW + AZD6244 75 mg BID<br>Participants receive MK-2206 90 mg oral tablets QW PLUS AZD6244 75 mg oral capsules BID starting on Day 1 of each 28-day cycle. | Drug: MK-2206<br>* Oral tablets<br>Drug: AZD6244<br>* Oral capsules<br>* Other names: selumetinib;|
| Experimental: MK-2206 90 mg QW + AZD6244 100 mg QD<br>Participants receive MK-2206 90 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. | Drug: MK-2206<br>* Oral tablets<br>Drug: AZD6244<br>* Oral capsules<br>* Other names: selumetinib;|
| Experimental: MK-2206 90 mg QW + AZD6244 150 mg QD<br>Participants receive MK-2206 90 mg oral tablets QW PLUS AZD6244 150 mg oral capsules QD starting on Day 1 of each 28-day cycle. | Drug: MK-2206<br>* Oral tablets<br>Drug: AZD6244<br>* Oral capsules<br>* Other names: selumetinib;|
| Experimental: MK-2206 100 mg QW + AZD6244 100 mg QD<br>Participants receive MK-2206 100 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. | Drug: MK-2206<br>* Oral tablets<br>Drug: AZD6244<br>* Oral capsules<br>* Other names: selumetinib;|
| Experimental: MK-2206 135 mg QW + AZD6244 100 mg QD<br>Participants receive MK-2206 135 mg oral tablets QW PLUS AZD6244 100 mg oral capsules QD starting on Day 1 of each 28-day cycle. | Drug: MK-2206<br>* Oral tablets<br>Drug: AZD6244<br>* Oral capsules<br>* Other names: selumetinib;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Dose-limiting Toxicity (DLT) | Adverse events (AEs) were graded using Common Terminology Criteria for Adverse Events (CTCAE), version 3.0. DLTs included: Grade 4 neutropenia lasting for ≥7 days; Grade 3 or Grade 4 neutropenia with fever >38.5ºC and/or infection requiring antibiotic or anti-fungal treatment; Grade 4 thrombocytopenia (≤25.0 x 10^9/L); Grade ≥3 non-hematologic toxicity with exceptions; Any drug-related AE, regardless of CTCAE Grade, leading to a dose modification of MK-2206 or AZD6244; Unresolved CTCAE Grade ≥3 drug-related toxicity requiring drug interruption for >14 days; ≥ Grade 3 signs or symptoms of glucose intolerance and accompanied by ≥ Grade 2 hyperglycemia (glucose >160 dL or 8.9 mmol/L); ≥ Grade 3 electrolyte abnormalities due to glucose intolerance and not attributable to another cause; Diagnosis of lactoacidosis or ketoacidosis; Persistent increases in corrected QT (QTc) interval (>60 msec from baseline and/or >500 msec); Clinically significant bradycardia. | Cycle 1 (Up to 28 days) | 
| Number of Participants Who Experienced at Least One Adverse Event (AE) | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening of a pre-existing condition which was temporally associated with the use of study drug was also an AE. The number of participants who experienced at least one AE is presented. | Up to approximately 23 months | 
| Number of Participants Who Discontinued Study Treatment Due to an AE | An AE was defined as any unfavorable and unintended change in the structure, function, or chemistry of the body temporally associated with the use of study drug, whether or not considered related to the use of the product. Any worsening of a pre-existing condition which was temporally associated with the use of study drug was also an AE. The number of participants who discontinued study treatment due to an AE is presented. | Up to approximately 20 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With a Tumor Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) | Radiological evaluation (via computed tomography [CT] or magnetic resonance imaging [MRI]) of tumor response was assessed every 8 weeks post-treatment during Cycles 1-6, and per institutional standard of care in Cycle 7 and beyond. The best overall tumor response was the best response based on RECIST 1.1 recorded from the start of the study treatment until the end of treatment. Response categories included: Complete Response (CR): Disappearance of all target lesions; Partial Response (PR): At least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): At least a 20% increase in the sum of diameters of target lesions; and Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD. Participants whose tumor was not evaluable (NE) were missing a valid RECIST1.1 measurement at baseline. The best overall tumor response for participants is presented. | Baseline and after every 8 weeks of treatment until documentation of objective response or disease progression (Up to 2 years) |