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

Locally Advanced or Metastatic Solid Tumors Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01021748
• Other study ID #: 2206-010
• Secondary ID: 2009_698
• Status: Completed
• Phase: Phase 1
• Start date: November 23, 2009
• Est. completion date: July 16, 2014

Study information

• Verified date: November 2017
• Source: Merck Sharp & Dohme Corp.
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 63
• Est. completion date: July 16, 2014
• Est. primary completion date: November 26, 2012
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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

Related Conditions & MeSH terms

• Locally Advanced or Metastatic Solid Tumors

Intervention

Drug:
• MK-2206
Oral tablets
• AZD6244
Oral capsules

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Merck Sharp & Dohme Corp.	AstraZeneca

References & Publications (1)

Tolcher AW, Khan K, Ong M, Banerji U, Papadimitrakopoulou V, Gandara DR, Patnaik A, Baird RD, Olmos D, Garrett CR, Skolnik JM, Rubin EH, Smith PD, Huang P, Learoyd M, Shannon KA, Morosky A, Tetteh E, Jou YM, Papadopoulos KP, Moreno V, Kaiser B, Yap TA, Ya — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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)
Primary	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
Primary	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	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)