| Eligibility |
Inclusion Criteria:
1. Be willing and able to provide written informed consent for the trial.
2. Be >/= 18 years of age on day of signing informed consent.
3. Evidence of PTEN loss in tumors by IHC or molecular analysis.
4. Have measurable disease based on RECIST 1.1.
5. Have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG)
Performance Scale.
6. Patients who have unresectable Stage III through stage IV metastatic cancer who have
not achieved complete or partial response after 6 months of therapy or who have
progressed on PD-L1 or PD-1 directed therapy including combinations. The Phase II
portion eligibility will be restricted to patients with metastatic melanoma.
7. In Phase I, Patients are allowed to have more than three prior systemic therapeutic
regimens. Patients enrolled to Phase II, can have no more than three prior systemic
therapeutic regimen for unresectable stage III or stage IV metastatic cancer. This
includes chemotherapy, biologic therapy, biochemotherapy, or investigational
treatment. This does not include any therapies given in the adjuvant setting.
8. Have a life expectancy of at least 12 weeks.
9. Have not received any chemotherapeutic, biological, investigational agent, radiation
therapy, or used an investigational device within 28 days of study drug
administration.
10. Able to swallow and retain orally administered medication.
11. On the dose expansion and Phase II portions of the study, patients must be willing to
provide tissue from a newly obtained core or excisional biopsy of a tumor lesion
before and at least one time point while on therapy. Correlative biopsies will be
optional in the Phase I portion of the study. Newly-obtained is defined as a specimen
obtained up to 6 weeks (42 days) prior to initiation of treatment on Day 1 without
intervening systemic therapy.
12. Within 10 days of treatment initiation, the subject must demonstrate adequate organ
function defined as follows: Absolute neutrophil count must be >/= 1500 per microliter
(uL). Platelets must be >/=100,000 per uL. Hemoglobin must be >/= 9 grams per
deciliter or >/= 5.6 millimoles per liter without transfusion or EPO dependency within
7 days of assessment. Serum creatinine must be </= 1.0 times the upper limit of normal
(ULN) OR measured or calculated creatinine clearance per institutional standard
(Glomerular Filtration Rate (GFR) can also be used in place of creatinine or CrCl)
must be >/= 60 milliliters per minute OR proteinuria by urine dipstick must be </= 1+.
Aspartate aminotransferase (AST) AND alanine aminotransferase (ALT) must be </= 2.5
times the ULN OR each must be </= 5 times the ULN for subjects with liver metastases.
Alkaline phosphatase (ALP) must be </= 2 times the ULN. Serum
13. Cont#12 total bilirubin must be </= 2.0 milligrams per deciliter except in patients
with Gilbert's disease. Direct bilirubin must be </= the upper limit of normal for
subjects with total bilirubin levels > 1.5 times the upper limit of normal. Albumin
must be >/= 2.5 grams per deciliter. Left ventricular ejection fraction (LVEF) must be
>/= 50% by echocardiogram (ECHO) or Multigated Acquisition (MUGA) scan. International
Normalized Ratio (INR) must be </= 1.5 times the upper limit of normal unless the
subject is receiving anticoagulant therapy as long as prothrombin time(PT) or partial
thromboplastin time(PTT) is within therapeutic range of intended use of
anticoagulants.Activated partial thromboplastin time(aPTT) must be </= 1.5 times the
upper limit of normal unless the subject is receiving anticoagulant therapy as long as
PT or PTT is within therapeutic range of intended use of anticoagulants. Serum
phosphate must be within normal limit. Serum calcium must be within normal limit
14. Female subject of childbearing potential should have a negative urine or serum
pregnancy within 72 hours prior to receiving the first dose of study medication. If
the urine test is positive or cannot be confirmed as negative, a serum pregnancy test
will be required.
15. Female subjects of childbearing potential must be willing to use an adequate method of
contraception for the course of the study through 4 months after the last dose of
study medication. Note: Abstinence is acceptable if this is the usual lifestyle and
preferred contraception for the subject.
16. Male subjects with a female partner of childbearing potential must agree to use
acceptable methods of contraception from the time of Screening until 3 months after
the last dose of study treatments.
Exclusion Criteria:
1. Patients are excluded if they have a history of or active autoimmune disease, as
follows: Patients with a history of inflammatory bowel disease are excluded from this
study as are patients with a history of symptomatic disease (e.g., rheumatoid
arthritis, systemic progressive sclerosis [scleroderma], Systemic Lupus Erythematosus,
autoimmune vasculitis [e.g., Wegener's Granulomatosis]). Patients with motor
neuropathy considered of autoimmune origin (e.g., Guillain-Barre Syndrome and
Myasthenia Gravis) are excluded. Patients with a history of autoimmune thyroiditis are
eligible if their current thyroid disorder is treated and stable with replacement or
other medical therapy.
2. Has active infections or serious general medical conditions (such as active myocardial
infarction (MI), cerebrovascular accident (CVA), or respiratory failure).
3. Any unresolved > Grade 1 toxicity (per CTCAE 4.0) from previous anti-cancer therapy or
previously administered agent at the time of enrollment, except for alopecia, Grade 2
anemia (if hemoglobin is >9 grams per deciliter (g/dL)) Note: If the subject received
major surgery, they must have recovered adequately from the toxicity and/or
complications from the intervention prior to starting therapy.
4. Presence of any clinically significant gastrointestinal (GI) abnormality or other
condition(s) that may alter absorption such as malabsorption syndrome or major
resection of the stomach or substantial portion of the small intestine.
5. Active peptic ulcer disease or history of abdominal fistula, GI perforation, or intra
abdominal abscess within 28 days prior to enrollment
6. Previous major surgery within 28 days prior to enrollment.
7. Evidence of severe or uncontrolled systemic diseases (e.g., unstable or uncompensated
respiratory, hepatic, renal or cardiac disease).
8. Has a QTc >450 milliseconds (msec) or QTc >480 msec for subjects with bundle branch
block (BBB) NOTES: The QTc is the QT interval corrected for heart rate by Bazett's
formula (QTcB), Fridericia's formula (QTcF), and/or another method, machine-read or
manually over-read. The specific formula that will be used to determine eligibility
and discontinuation for an individual subject should be determined prior to initiation
of the study. In other words, several different formulae cannot be used to calculate
the QTc for an individual subject and then the lowest QTc value used to include or
discontinue the subject from the trial. For purposes of data analysis QTcF will be
used.
9. History or evidence of cardiovascular risk including any of the following: -
Clinically significant electrocardiogram (ECG) abnormalities including second degree
(Type II) or third degree atrioventricular block - History of myocardial infarction,
acute coronary syndromes (including unstable angina), coronary angioplasty, stenting,
or bypass grafting within the past 6 months prior to enrollment - Class III or IV
heart failure as defined by the New York Heart Association (NYHA) functional
classification system - Left ventricular ejection fraction (LVEF) below 50% - Known
cardiac metastases.
10. Poorly controlled hypertension (defined as systolic blood pressure [SBP] of >/= 150
millimeters of mercury (mmHg) or diastolic blood pressure [DBP] of >100 mmHg based on
a mean of three measurements at approximately 2-minute intervals) NOTE: Initiation or
adjustment of antihypertensive medication(s) is permitted if done thirty or more days
prior to enrollment.
11. History of congenital platelet function defect (e.g., Bernard-Soulier syndrome,
Chediak-Higashi syndrome, Glanzmann thrombasthenia, storage pool defect)
12. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any
other form of immunosuppressive therapy within 7 days prior to the first dose of trial
treatment. NOTE: Replacement dose steroids (equivalent to 10 mg prednisone) are
allowed.
13. Has a known history of active TB (Bacillus Tuberculosis).
14. Hypersensitivity to Pembrolizumab or GSK2636771 or excipients.
15. Has a known prior or additional malignancy that is progressing or requires active
treatment. Exceptions include basal cell carcinoma of the skin or squamous cell
carcinoma of the skin that has undergone potentially curative therapy or in situ
cervical cancer.
16. Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least two weeks
prior to the first dose of trial treatment and any neurologic symptoms have returned
to baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.
17. Has a history of (non-infectious) pneumonitis that required steroids or current
pneumonitis.
18. Has a history or current evidence of any condition, therapy, or laboratory abnormality
that might confound the results of the trial, interfere with the subject's
participation for the full duration of the trial, or is not in the best interest of
the subject to participate, in the opinion of the treating investigator.
19. Has known psychiatric or substance abuse disorders that in the opinion of the
registering physician or PI would interfere with cooperation with the requirements of
the trial.
20. Has a known history or positive test for Human Immunodeficiency Virus (HIV) (HIV 1/2
antibodies). Testing at the time of Screening is not required.
21. Presence of hepatitis B surface antigen (HBsAg), positive hepatitis C antibody test
result at time of Screening or any history of hepatitis.
22. Has received a live vaccine within 30 days of planned start of study therapy.
23. Current use of or anticipated requirement during the study of any prohibited
medication(s). Note: Seasonal influenza vaccines for injection are generally
inactivated flu vaccines and are allowed; however intranasal influenza vaccines (e.g.,
Flu-Mist®) are live attenuated vaccines, and are not allowed.
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