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

This study is currently recruiting participants.
Verified February 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: February 7, 2014
Last verified: February 2014
  Purpose

This phase II trial studies how well Akt inhibitor MK2206 works in treating patients with previously treated colon or rectal cancer that is metastatic or 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
Mucinous Adenocarcinoma of the Colon
Mucinous Adenocarcinoma of the Rectum
Recurrent Colon Cancer
Recurrent Rectal Cancer
Signet Ring Adenocarcinoma of the Colon
Signet Ring Adenocarcinoma of the Rectum
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 RECIST 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 2014 (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. Courses repeat 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 phosphatase and tensin homolog (PTEN), v-raf murine sarcoma viral oncogene homolog B1 (BRAF), PIK3CA, and v-akt murine thymoma viral oncogene homolog 1 (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. Courses repeat 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 unresectable colorectal adenocarcinoma that is amenable to image-guided biopsy and for which standard curative or palliative measures do not exist or are no longer effective; disease in previously radiated regions may not be considered measurable unless there has been demonstrated progression in the lesion
  • Patients must have failed available therapy for the treatment of advanced colorectal cancer; this is defined as progressive disease during or within 6 months after fluoropyrimidine, irinotecan, oxaliplatin, bevacizumab, and for v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) wild-type patients, anti-epidermal growth factor receptor (EGFR) antibody (cetuximab or panitumumab) containing therapies, with most recent progression by Response Evaluation Criteria in Solid Tumors (RECIST) criteria; patients who had at least stable disease as best response on their prior therapies (listed above) should have received at least 2 months (approximately 60 days) of treatment; for oxaliplatin-based therapy, failure of therapy will also include patients who progressed within 12 months of adjuvant therapy and patients who had oxaliplatin stopped due to toxicity
  • 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 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
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: February 7, 2014
Health Authority: United States: Food and Drug Administration

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

ClinicalTrials.gov processed this record on April 17, 2014