A Phase II Study of Akt Inhibitor MK2206 in the Treatment of Recurrent Platinum-Resistant Ovarian, Fallopian Tube, or Peritoneal Cancer
Condition: Ovarian Sarcoma; Recurrent Fallopian Tube Carcinoma; Recurrent Ovarian Carcinoma; Recurrent Primary Peritoneal Carcinoma
MeSH terms: Carcinoma; Recurrence
Intervention: Akt Inhibitor MK2206; Laboratory Biomarker Analysis
Intervention description: Given PO; Correlative studies
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 6.0
Sex: Female
Minimum age: 18 Years
Healthy volunteers: No

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.
    

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