Brief Title
A Phase II Study of Akt Inhibitor MK2206 in the Treatment of Recurrent Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer
Official Title
A Phase II Study of MK-2206 in the Treatment of Recurrent High-Grade Serous Platinum-Resistant Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Brief Summary
Akt inhibitor MK2206 is a drug that may stop cancer cells from growing by blocking a protein
called protein kinase B (AKT) inside the cell. AKT interacts with other proteins in the cell
that are part of the P13K/AKT pathway, a pathway that is know to play a role in the growth of
cancer cells. Mutations in P13K or in AKT, or changes in another protein called phosphatase
and tensin homolog (PTEN) in this pathway can lead it to become more active than is normal.
This study investigates how effective MK-2206 is in treating ovarian, fallopian tube, or
primary peritoneal cancer where there are mutations in P13K or AKT or low levels of PTEN.
Detailed Description
PRIMARY OBJECTIVES:
I. To assess the activity of MK-2206 (Akt inhibitor MK2206) in patients with recurrent grade
2 or 3 platinum-resistant high-grade serous ovarian, fallopian tube, or peritoneal cancer, as
measured by the frequency of patients experiencing an objective tumor response by Response
Evaluation Criteria In Solid Tumors (RECIST) criteria or who survive progression-free for at
least 6 months after initiation of therapy.
SECONDARY OBJECTIVES:
I. To assess the duration of progression-free and overall survival following initiation of
therapy with MK-2206 in the cohort of patients enrolled on this study.
II. To determine the toxicities of MK-2206, as assessed by the active version of the National
Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0 III. To
explore the association between select biomarkers and response to MK-2206 (as assessed by
objective tumor response, progression-free survival, and overall survival) IV. To explore the
development of feedback loop activation and target inhibition with MK-2206 via analysis of
pre-treatment and post-treatment biopsies in select patients enrolled in the trial.
OUTLINE:
Akt inhibitor MK2206 will be taken orally (PO) once a week for four weeks (one cycle).
Treatment will continue for as long as a subject is benefiting from the study drug.
During each cycle subjects will have a physical exam, blood samples and an electrocardiogram
(EKG) (first 2 cycles). Every 2 cycles a computed tomography (CT) scan or magnetic resonance
imaging (MRI) of chest, stomach area, and pelvis will be performed. Optional tumor biopsies
may be performed.
Study Phase
Phase 2
Study Type
Interventional
Primary Outcome
Efficacy (as Measured by Objective Response Rate) of Akt Inhibitor MK2206 in Patients With Recurrent High-grade Platinum-resistant Serous Ovarian, Fallopian Tube, or Primary Peritoneal Cancer
Secondary Outcome
Association Between Select Biomarkers and Response to Akt Inhibitor MK2206 (as Assessed by Objective Tumor Response, Progression-free Survival, and Overall Survival)
Condition
Ovarian Sarcoma
Intervention
Akt Inhibitor MK2206
Study Arms / Comparison Groups
Treatment (Akt inhibitor MK2206)
Description: Akt inhibitor MK2206 will be taken PO once a week for four weeks (one cycle). Treatment will continue for as long as a subject is benefiting from the study drug.
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
6
Start Date
April 2011
Completion Date
December 2014
Primary Completion Date
December 2014
Eligibility Criteria
Inclusion Criteria:
- Participants must have histologically or cytologically confirmed high grade (grade 2
or 3) serous ovarian, fallopian tube, or primary peritoneal cancer; participants with
mixed histology are eligible if the serous component is the dominant histological
subtype
- Participants must have measurable disease as defined by RECIST 1.1 criteria
- Participants must have evidence of a defect in the PI3K/AKT pathway, defined by A)
evidence of loss of PTEN by immunohistochemistry in a CLIA-certified assay or B)
documentation of PIK3CA or AKT mutation in a CLIA-certified assay; for patients
without prior CLIA-certified evidence of a PI3K/AKT pathway defect, PTEN testing will
be performed by immunohistochemistry in a CLIA-certified assay; availability of a
formalin fixed paraffin embedded (FFPE) block of cancer tissue from the original or
most recent biopsy must be available for mutational and immunohistochemical analysis
- Prior therapy:
- Prior chemotherapy must have included a first-line platinum-based regimen with or
without consolidation chemotherapy
- Patients may have received up to 2 lines of therapy (including cytotoxic or
biological and/or targeted therapies) in the recurrent setting
- Prior hormonal therapy is acceptable and will not count as an additional line of
therapy
- Patients may not have previously received prior AKT or PI3 kinase pathway
inhibitors (including mTOR inhibitors)
- Patients should have platinum-resistant disease, where platinum resistance is
defined as having progressive disease within 6 months of receipt of prior
platinum therapy
- Life expectancy of greater than 6 months
- Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky > 60%)
- Absolute neutrophil count >= 1,500/mcL
- Platelets >= 100,000/mcL
- Hemoglobin >= 8.0 g/dL
- Total bilirubin within normal institutional limits
- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamic pyruvate transaminase [SGPT]) <
2.5 X institutional upper limit of normal
- Creatinine within normal institutional limits or creatinine clearance > 60 mL/min/1.73
m^2 for subjects with creatinine levels about institutional normal
- Toxicities of prior therapy (excepting alopecia) should be resolved to less than or
equal to grade 1 as per NCI-CTCAE v4.0
- Patients must be able to tolerate oral medications and not have gastrointestinal
illnesses that would preclude absorption of MK-2206
- The effects of MK-2206 on the developing human fetus are unknown; for this reason,
women of child-bearing potential must agree to use adequate contraception (hormonal or
barrier method of birth control; abstinence) prior to study entry and for the duration
of study participation; should a woman become pregnant or suspect she is pregnant
while participating in this study, she should inform her treating physician
immediately
- Ability to understand and the willingness to sign a written informed consent document
Exclusion Criteria:
- Participants who exhibit any of the following conditions at screening will not be
eligible for admission into the study
- Participants who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered to grade 1 or less (excepting alopecia) due to agents administered more than
4 weeks earlier
- Participants may not be receiving any other study agents
- Participants with known brain metastases should be excluded from this clinical trial
because of their poor prognosis and because they often develop progressive neurologic
dysfunction that would confound the evaluation of neurologic and other adverse events
- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to MK-2206
- Participants receiving any medications or substances that are strong inhibitors or
inducers of CYP450 3A4 are ineligible; lists including medications and substances
known or with the potential to interact with the CYP450 3A4 isoenzymes are provided in
Appendix C; if the participant is taking any agent known to affect or with the
potential to affect CYP450 3A4 isoenzymes, this should be discussed with the overall
PI
- Preclinical studies demonstrated the potential of MK-2206 for induction of
hyperglycemia in all preclinical species tested; patients with diabetes or at risk for
hyperglycemia are eligible for this study, but the hyperglycemia should be well
controlled on oral agents before the patient enters the trial; a fasting serum glucose
of > 130 mg/dL or a HgbA1c > 7.5 mg/dL will exclude patients from entry on study;
patients requiring insulin for control of their hyperglycemia are excluded from entry
on this study
- Preclinical studies indicated transient changes in QTc interval during MK-2206
treatment; prolongation of QTc interval is potentially a safety concern while on
MK-2206 therapy; cardiovascular: baseline QTcF > 450 msec (male) or QTcF > 470 msec
(female) will exclude patients from entry on study; a list of medications that may
cause QTc interval prolongation are listed in Appendix D, and should be avoided by
patients entering on trial
- Due to a high incidence of bradycardia by Holter monitor, preexisting significant
heart block or baseline bradycardia due to cardiac disease will exclude patients from
treatment with MK-2206
- 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
- Current signs and/or symptoms of bowel obstruction
- Current dependency on IV hydration or TPN
- Pregnant women are excluded from this study because MK-2206 is an agent with the
potential for teratogenic or abortifacient effects; because there is an unknown but
potential risk of adverse events in nursing infants secondary to treatment of the
mother with MK-2206, breastfeeding should be discontinued if the mother is treated
with MK-2206; these potential risks may also apply to other agents used in this study
- Individuals with a history of a different malignancy are ineligible except for the
following circumstances; individuals with a history of other malignancies are eligible
if they have been disease-free for at least 5 years and are deemed by the investigator
to be at low risk for recurrence of that malignancy; individuals with the following
cancers are eligible if diagnosed and treated within the past 5 years: breast cancer
in situ, cervical cancer in situ, and basal cell or squamous cell carcinoma of the
skin
- Human immunodeficiency virus (HIV)-positive individuals on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
MK-2206; iIn addition, these individuals are at increased risk of lethal infections
when treated with marrow-suppressive therapy; appropriate studies will be undertaken
in participants receiving combination antiretroviral therapy when indicated
- Patients may not use natural herbal products or other "folk remedies" while
participating in this study
Gender
Female
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
Joyce Liu, ,
Location Countries
United States
Location Countries
United States
Administrative Informations
NCT ID
NCT01283035
Organization ID
NCI-2013-00549
Secondary IDs
NCI-2013-00549
Responsible Party
Sponsor
Study Sponsor
National Cancer Institute (NCI)
Study Sponsor
Joyce Liu, Principal Investigator, Dana-Farber Cancer Institute
Verification Date
May 2016