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

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
ClinicalTrials.gov Identifier: NCT01021748
Recruitment Status : Completed
First Posted : November 30, 2009
Results First Posted : August 7, 2018
Last Update Posted : August 7, 2018
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
Merck Sharp & Dohme Corp.

Brief Summary:

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.


Condition or disease Intervention/treatment Phase
Locally Advanced or Metastatic Solid Tumors Drug: MK-2206 Drug: AZD6244 Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 63 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Study of Oral MK-2206 in Combination With Oral AZD6244 in Patients With Locally Advanced or Metastatic Solid Tumors
Actual Study Start Date : November 23, 2009
Actual Primary Completion Date : November 26, 2012
Actual Study Completion Date : July 16, 2014

Arm Intervention/treatment
Experimental: MK-2206 45 mg QOD + AZD6244 75 mg QD
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
Oral tablets

Drug: AZD6244
Oral capsules
Other Name: selumetinib

Experimental: MK-2206 45 mg QOD + AZD6244 75 mg BID
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
Oral tablets

Drug: AZD6244
Oral capsules
Other Name: selumetinib

Experimental: MK-2206 90 mg QW + AZD6244 50 mg BID
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
Oral tablets

Drug: AZD6244
Oral capsules
Other Name: selumetinib

Experimental: MK-2206 90 mg QW + AZD6244 75 mg QD
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
Oral tablets

Drug: AZD6244
Oral capsules
Other Name: selumetinib

Experimental: MK-2206 90 mg QW + AZD6244 75 mg BID
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
Oral tablets

Drug: AZD6244
Oral capsules
Other Name: selumetinib

Experimental: MK-2206 90 mg QW + AZD6244 100 mg QD
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
Oral tablets

Drug: AZD6244
Oral capsules
Other Name: selumetinib

Experimental: MK-2206 90 mg QW + AZD6244 150 mg QD
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
Oral tablets

Drug: AZD6244
Oral capsules
Other Name: selumetinib

Experimental: MK-2206 100 mg QW + AZD6244 100 mg QD
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
Oral tablets

Drug: AZD6244
Oral capsules
Other Name: selumetinib

Experimental: MK-2206 135 mg QW + AZD6244 100 mg QD
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
Oral tablets

Drug: AZD6244
Oral capsules
Other Name: selumetinib




Primary Outcome Measures :
  1. Number of Participants With a Dose-limiting Toxicity (DLT) [ Time Frame: Cycle 1 (Up to 28 days) ]
    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.

  2. Number of Participants Who Experienced at Least One Adverse Event (AE) [ Time Frame: Up to approximately 23 months ]
    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.

  3. Number of Participants Who Discontinued Study Treatment Due to an AE [ Time Frame: Up to approximately 20 months ]
    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.


Secondary Outcome Measures :
  1. Number of Participants With a Tumor Response According to Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) [ Time Frame: Baseline and after every 8 weeks of treatment until documentation of objective response or disease progression (Up to 2 years) ]
    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.



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01021748


Sponsors and Collaborators
Merck Sharp & Dohme Corp.
AstraZeneca
Investigators
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Study Director: Medical Director Merck Sharp & Dohme Corp.

Publications of Results:
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Responsible Party: Merck Sharp & Dohme Corp.
ClinicalTrials.gov Identifier: NCT01021748     History of Changes
Other Study ID Numbers: 2206-010
2009_698 ( Other Identifier: Merck Registration Number )
First Posted: November 30, 2009    Key Record Dates
Results First Posted: August 7, 2018
Last Update Posted: August 7, 2018
Last Verified: November 2017

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No