Phase IB of Selinexor in Combination With Standard Chemotherapy in Patients With Advanced Malignancies

Primary Outcome Measures

• Maximum Tolerated Dose (MTD) [ Time Frame: 21 or 28 days depending on the arm assignment ]
  MTD defined as the highest dose level with an observed incidence of dose limiting toxicity (DLT) in ≤ 33% of patients enrolled in a dose escalation cohort.

Secondary Outcome Measures

• Disease Control [ Time Frame: 6 months ]
  Disease control defined as complete response, partial response + stable disease for at least 6 months, measured by objective tumor response according to RECIST 1.1 criteria.

Detailed Description

This is an open label, single center Phase IB combination therapy study in metastatic or locally advanced cancers. The addition of Selinexor to multiple standard chemotherapy regimens will be tested in parallel. Two types of patients may be enrolled in this study: (1) advanced staged cancer patients either unresponsive or relapsed following prior standard therapy or for whom there is no known effective therapy; OR (2) advanced stage cancer patients for whom the standard chemotherapy treatment to which Selinexor is added is considered an appropriate and acceptable therapy. Patients who meet these criteria may in some cases have received no prior chemotherapy.

Eligibility

Inclusion Criteria

Patients must have histologically or cytologically confirmed malignant neoplasms (not including hematological malignancies and brain tumors) untreated or previously treated requiring further treatment. Patients must be refractory to, and intolerant of, established therapy known to provide clinical benefit for their condition.

Patients must have failed prior standard curative chemotherapy for their disease. Subjects must have failed, be intolerant to, or be ineligible for any potentially curative approved treatment, irrespective of line of therapy.

Patients must have either measurable disease (RECIST 1.1) or evaluable disease (non-measurable lesions) outside irradiated field on CT/MRI.

Age >/= 18 years.

Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

The patient must be recovered from a prior major surgery. The major surgery must be performed at least 4 weeks prior to consent date.

Adequate hematologic function defined as: platelets >/=125 x 10^9/L (For Arm L Pembrolizumab, platelets >/= 100 x 10^9/L), hemoglobin >/= 10 g/dL (For Arm L Pembrolizumab, hemaglobin >/= 9 g/dL), ANC >/= 1.5 x 10^9/L, WBC >/= 3 x 10^9/L, Albumin >/= 3 g/dL. Transfusions and growth factors are allowed.

Adequate liver function defined as: Alanine transaminase (ALT) Renal function defined as a calculated or measured glomerular filtration rate (GFR) >/=30 mL/min. For Arm F Carboplatin and Pemetrexed, GFR >/=45 mL/min.

The patient has recovered to Grade Life expectancy of at least 12 weeks

Able to swallow and retain oral medication.

Patients must give informed consent according to the rules and regulations of the individual participating sites.

Negative serum pregnancy test in women of childbearing potential within 7 days of first dose of treatment and patients of child-bearing potential must agree to use effective contraception during/after 3 months post dose. A woman of childbearing potential is defined as a premenopausal female capable of becoming pregnant. This includes women on oral, injectable or mechanical contraception; women who are single and women whose male sexual partners have been vasectomized or whose male sexual partners have received or are utilizing mechanical contraceptive devices.

If in Arm D (Doxorubicin and Cyclophosphamide), left ventricular ejection fraction (LVEF) >/= 50% as measured by echocardiogram (ECHO) within 4 weeks prior to study drug administration.

Exclusion Criteria

Evidence of complete or partial bowel obstruction.

Patients with primary CNS tumor or CNS tumor involvement. However, patients with metastatic CNS tumors may participate in this study if the patient is: > 4 weeks from prior therapy completion (including radiation and/or surgery); Clinically stable with respect to the CNS tumor at the time of study entry; Not receiving steroid therapy in treating CNS tumor or CNS tumor involvement; Not receiving anti-convulsive medications (that were started for brain metastases).

Need of Total Parenteral Nutrition.

Prior treatment with an agent targeting the Exportin.

Allergic to Selinexor or any of the chemotherapy intended to receive.

Pregnancy or lactation.

Radiation (except planned or ongoing palliative radiation to bone outside of the region of measurable disease) Chemotherapy, or immunotherapy or any other systemic anticancer therapy Diagnosis or recurrence of invasive cancer other than the present cancer within 3 years (except basal or squamous cell carcinoma of the skin that has been definitively treated).

Major surgery within four weeks before consent date.

Unstable cardiovascular function: Symptomatic ischemia (chest pain of cardiac origin), or Uncontrolled clinically significant conduction abnormalities (e.g. ventricular tachycardia on antiarrhythmics are excluded and 1st degree AV block or asymptomatic LAFB/ RBBB will not be excluded), or Congestive heart failure (CHF) of NYHA Class >/= 3, or Myocardial infarction (MI) within 3 months of consent date.

Uncontrolled active infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to the first dose. Active infection with concurrent treatment is acceptable only if the patient is clinically stable.

Significantly diseased (as determined by the PI or treating physician) or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea.

Treatment with an investigational anti-cancer study drug within 3 weeks prior to study drug administration date.

Concurrent therapy with approved or investigational anticancer therapeutics.

Medical, psychological or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results

Men whose partner is a woman of child-bearing potential, (i.e. biologically able to conceive), and who is not employing two forms of highly effective contraception. Highly effective contraception (e.g. male condom with spermicide, diaphragm with spermicide, intra-uterine device) must be used by both sexes during the study and must be continued for 3 months after the end of study treatment. Women of child-bearing potential is defined as sexually mature women who are not surgically sterile or who have not been naturally postmenopausal for at least 12 consecutive months (e.g., who has had menses any time in the preceding 12 consecutive months).

If in Arm D (Doxorubicin and Cyclophosphamide), patients with prior cumulative doxorubicin dose of >/= 260 mg/m2.

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