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Akt Inhibitor MK2206 in Treating Patients With Previously Treated Colon or Rectal Cancer That is Metastatic or Locally Advanced and Cannot Be Removed by Surgery

This study is currently recruiting participants. (see Contacts and Locations)
Verified June 2014 by National Cancer Institute (NCI)
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)
ClinicalTrials.gov Identifier:
NCT01802320
First received: February 27, 2013
Last updated: November 21, 2014
Last verified: June 2014
  Purpose

This phase II trial studies how well v-akt murine thymoma viral oncogene homolog 1 (Akt) inhibitor MK2206 works in treating patients with previously treated colon or rectal cancer that has spread from the primary site to other places in the body or nearby tissue or lymph nodes and cannot be removed by surgery. Akt inhibitor MK2206 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.


Condition Intervention Phase
Colon Mucinous Adenocarcinoma
Colon Signet Ring Cell Adenocarcinoma
Rectal Mucinous Adenocarcinoma
Rectal Signet Ring Cell Adenocarcinoma
Recurrent Colon Carcinoma
Recurrent Rectal Carcinoma
Stage IIIA Colon Cancer
Stage IIIA Rectal Cancer
Stage IIIB Colon Cancer
Stage IIIB Rectal Cancer
Stage IIIC Colon Cancer
Stage IIIC Rectal Cancer
Stage IVA Colon Cancer
Stage IVA Rectal Cancer
Stage IVB Colon Cancer
Stage IVB Rectal Cancer
Drug: Akt Inhibitor MK2206
Other: Laboratory Biomarker Analysis
Other: Pharmacological Study
Phase 2

Study Type: Interventional
Study Design: Endpoint Classification: Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase 2 Study of MK-2206 in Previously Treated Metastatic Colorectal Cancer Patients Enriched for PTEN Loss and PIK3CA Mutation

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Overall response rate (CR+PR) evaluated using Response Evaluation Criteria in Solid Tumors version 1.1 [ Time Frame: Up to 18 months ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Validation of the enrichment biomarker signature in metastatic sites [ Time Frame: Up to 18 months ] [ Designated as safety issue: No ]
    Samples will be analyzed using the Wilcoxon rank test. Chi-square or Fisher's exact test where appropriate will be used to determine whether high levels of marker expression correlate with PTEN status.

  • PFS [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 18 months ] [ Designated as safety issue: No ]
    Estimated using the Kaplan and Meier product limit method. Cox proportional hazards regression model will be used to identify prognostic factors for PFS.

  • OS [ Time Frame: Up to 18 months ] [ Designated as safety issue: No ]
    Estimated using the Kaplan and Meier product limit method. Cox proportional hazards regression model will be used to identify prognostic factors for OS.

  • DR [ Time Frame: From the time measurement criteria are met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 18 months ] [ Designated as safety issue: No ]
    Estimated using the Kaplan and Meier product limit method. Cox proportional hazards regression model will be used to identify prognostic factors for DR.


Estimated Enrollment: 54
Study Start Date: March 2013
Estimated Primary Completion Date: September 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (Akt inhibitor MK2206)
Patients receive Akt inhibitor MK2206 PO on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.
Drug: Akt Inhibitor MK2206
Given PO
Other Name: MK2206
Other: Laboratory Biomarker Analysis
Correlative studies
Other: Pharmacological Study
Correlative studies
Other Name: pharmacological studies

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the response rate to MK-2206 (Akt inhibitor MK2206), defined as complete response (CR) + partial response (PR).

SECONDARY OBJECTIVES:

I. To determine response rate to MK-2206 in patients with phosphatase and tensin homolog (PTEN) loss or phosphatidylinositol-4,5-bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) mutation in a pretreatment biopsy from a metastatic site.

II. To determine progression-free survival (PFS) and overall survival (OS). III. To determine the time to treatment failure (TTF), and duration of tumor response (DR).

IV. To determine the safety profile and tolerability of this regimen in this patient population.

V. To determine effect of PTEN, v-raf murine sarcoma viral oncogene homolog B1 (BRAF), PIK3CA, and AKT mutations and semi-quantitative grading of PTEN expression on clinical response.

OUTLINE:

Patients receive Akt inhibitor MK2206 orally (PO) on days 1, 8, 15, and 22. Treatment repeats every 28 days for up to 24 months in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 6 months.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients must have histologically confirmed, radiologically measurable metastatic or locally advanced unresectable colorectal adenocarcinoma that is amenable to image-guided biopsy; disease in previously radiated regions may not be considered measurable unless there has been demonstrated progression in the lesion
  • Patients must have progressed on or been intolerant to a fluoropyrimidine-based chemotherapy regimen; there is no limit on the number of prior treatment regimens permitted
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  • Life expectancy of greater than 12 weeks
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin =< institution upper limit of normal
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT]) =< 2.5 X institutional upper limit of normal or =< 5 X institutional upper limit of normal for patients with known liver metastasis
  • Creatinine =< institution upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Women of child-bearing potential and men must agree to use adequate contraception (double barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and 4 months after completion of MK-2206 administration; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of MK-2206 administration
  • Patients must be able to swallow whole tablets; nasogastric or gastrostomy (G) tube administration is not allowed; tablets must not be crushed or chewed
  • Ability to understand and the willingness to sign a written informed consent document
  • Tumor must be wild type for the v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) and BRAF oncogenes, and must have known PIK3CA, AKT mutation status and PTEN expression status

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study; if the patient has residual toxicity from prior treatment, toxicity must be =< grade 1 (or =< grade 2 for peripheral neuropathy and/or alopecia)
  • Patients who are receiving or have received any other investigational agents within 30 days of study day 1, or who have previously received MK-2206 at any time
  • Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis; however, patients with CNS metastases who have completed a course of therapy would be eligible for the study provided they are clinically stable for at least 1 month prior to entry as defined as:

    • No evidence of new or enlarging CNS metastasis
    • Off steroids that are used to minimize surrounding brain edema
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to MK-2206
  • Patients receiving any medications or substances that are inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP450 3A4) are ineligible
  • Patients with diabetes or in risk for hyperglycemia should not be excluded from trials with MK-2206, but the hyperglycemia should be well controlled on oral agents before the patient enters the trial
  • Cardiovascular baseline corrected QT by Fridericia's (QTcF) > 450 msec (male) or QTcF > 470 msec (female) will exclude patients from entry on study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with MK-2206
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01802320

Locations
United States, Texas
M D Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Edmund S. Kopetz    713-792-2828    skopetz@mdanderson.org   
Principal Investigator: Edmund S. Kopetz         
Sponsors and Collaborators
Investigators
Principal Investigator: Edmund Kopetz M.D. Anderson Cancer Center
  More Information

No publications provided

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT01802320     History of Changes
Other Study ID Numbers: NCI-2013-00487, NCI-2013-00487, 2012-0431, 9340, N01CM00039, P30CA016672
Study First Received: February 27, 2013
Last Updated: November 21, 2014
Health Authority: United States: Food and Drug Administration

Additional relevant MeSH terms:
Cystadenocarcinoma
Adenocarcinoma
Adenocarcinoma, Mucinous
Carcinoma
Carcinoma, Signet Ring Cell
Colonic Neoplasms
Rectal Neoplasms
Colonic Diseases
Colorectal Neoplasms
Digestive System Diseases
Digestive System Neoplasms
Gastrointestinal Diseases
Gastrointestinal Neoplasms
Intestinal Diseases
Intestinal Neoplasms
Neoplasms
Neoplasms by Histologic Type
Neoplasms by Site
Neoplasms, Cystic, Mucinous, and Serous
Neoplasms, Glandular and Epithelial
Rectal Diseases

ClinicalTrials.gov processed this record on November 23, 2014