Phase IB Study to Evaluate the Safety of Selinexor (KPT-330) in Combination With Multiple Standard Chemotherapy or Immunotherapy Agents in Patients With Advanced Malignancies

Inclusion Criteria:

• Patients must have histologically or cytologically confirmed malignant neoplasms (not including hematological malignancies and brain tumors) untreated or previouslytreated requiring further treatment; patients in Arm L (pembrolizumab), Arm M (nivolumab), and Arms N, O, P (nivolumab and ipilimumab) that have Food and DrugAdministration (FDA)-approved indications for nivolumab, ipilimumab, andpembrolizumab do not have to fail first line nivolumab, ipilimumab, orpembrolizumab, and these patients may be treatment naïve if they have disease wherepembrolizumab or nivolumab are FDA approved for the first-line setting

• For all arms except Arm L (pembrolizumab), Arm M (nivolumab), and Arms N, O, P (nivolumab and ipilimumab) patients must have failed prior standard curativechemotherapy for their disease; subjects must have failed, be intolerant to, or beineligible for any potentially curative approved treatment, irrespective of line oftherapy

• Patients must have measurable disease (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)

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

• The patient must be recovered from a prior major surgery; the major surgery must beperformed at least 4 weeks prior to consent date

• Platelets >= 125 x 10^9/L (For Arm L pembrolizumab, Arm M nivolumab and Arms N, O, P [nivolumab and ipilimumab] and expansion cohorts for all arms, platelets >= 100 x 10^9/L)

• Hemoglobin >= 10 g/dL (For Arm L pembrolizumab, Arm M nivolumab and Arms N, O, P [nivolumab and ipilimumab] and expansion cohorts for all arms, hemoglobin >= 9 g/dL)

• Absolute neutrophil count (ANC) >= 1.5 x 10^9/L (For Arm L pembrolizumab, Arm Mnivolumab and Arms N, O, P [nivolumab and ipilimumab], ANC >= 1.0 x 10^9/L)

• Transfusions and growth factors are allowed

• Alanine transaminase (alanine aminotransferase [ALT]) =< 2 x upper normal limit (ULN) (in the expansion cohort, patients with known liver involvement may have ALT =< 5 x ULN); aspartate aminotransferase (AST) =< 2 x ULN (in the expansion cohort,patients with known liver involvement may have AST =< 5 x ULN)

• Alkaline phosphatase < 4 x ULN

• Total bilirubin =< 2 x ULN (in the expansion cohort, patients with Gilbert'ssyndrome [hereditary indirect hyperbilirubinemia] who must have a total bilirubin of =< 3 x ULN)

• Renal function defined as a calculated or measured glomerular filtration rate (GFR) >= 30 mL/min. For patients with renal cell carcinoma (RCC), the GFR may be definedas >= 25 mL/min

• The patient has recovered to grade =< 1 by the National Cancer Institute CommonTerminology Criteria for Adverse Events, version 4.03 (NCI-CTCAE v4.03) from theeffects of recent surgery, radiotherapy, chemotherapy, hormonal therapy, or othertargeted therapies, with the exception of alopecia; the exceptions for such effectsare allowed lab values of =< grade 2 specified elsewhere in these inclusion criteria

• 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 theindividual participating sites

• Negative serum pregnancy test in women of childbearing potential within 7 days offirst dose of treatment and patients of child-bearing potential must agree to useeffective contraception during/after 3 months post dose; a woman of childbearingpotential is defined as a premenopausal female capable of becoming pregnant; thisincludes women on oral, injectable or mechanical contraception; women who are singleand women whose male sexual partners have been vasectomized or whose male sexualpartners have received or are utilizing mechanical contraceptive devices

• For the Arm B (paclitaxel) expansion cohort, patients must have ovarian carcinoma,fallopian tube, or peritonea carcinoma

• For Arm C (eribulin) expansion cohort, patients must have triple negative breastcancer (eribulin naive)

• For Arm M (nivolumab) expansion phase, patients must have biopsiable disease

• For the Arm N (nivolumab and ipilimumab), patients must have metastatic orunresectable renal cell carcinoma (RCC)

• For the Arm O (nivolumab and ipilimumab) escalation and expansion Cohort O-1,patients must have metastatic or unresectable melanoma

• For the Arm O (nivolumab and ipilimumab) expansion Cohort O-2, patients must havemetastatic or advanced solid tumors (non-melanoma, non-renal cell carcinoma, or non-non-small cell lung carcinoma)

• For the Arm P (nivolumab and ipilimumab), patients must have metastatic orunresectable non-small cell lung carcinoma (NSCLC)

Exclusion Criteria:

• Evidence of complete or partial bowel obstruction

• Patients with primary central nervous system (CNS) tumor or CNS tumor involvement;however, patients with metastatic CNS tumors may participate in this study if thepatient 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 brainmetastases)

• 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 theregion of measurable disease) =< 3 weeks prior to study drug administration date

• Chemotherapy, or immunotherapy or any other systemic anticancer therapy =< 3 weeksprior to study drug administration date; patients receiving anti-PD-1 treatment, andcontinue to receiving this treatment in combination with selinexor (Arms L, M, N, O,and P), can start receiving the selinexor and anti-PD-1 combination without washoutof the prior anti-PD-1 antibody

• Diagnosis or recurrence of invasive cancer other than the present cancer within 3years (except basal or squamous cell carcinoma of the skin that has beendefinitively treated)

• Major surgery within four weeks before consent date

• Unstable cardiovascular function: symptomatic ischemia (chest pain of cardiacorigin), or uncontrolled clinically significant conduction abnormalities (e.g.ventricular tachycardia on antiarrhythmics are excluded and 1st degreeatrioventricular [AV] block or asymptomatic left anterior fascicular block [LAFB]/right bundle branch block [RBBB] will not be excluded), or congestive heartfailure (CHF) of New York Heart Association (NYHA) class >= 3, or myocardialinfarction (MI) within 3 months of consent date

• Uncontrolled active infection requiring parenteral antibiotics, antivirals, orantifungals within one week prior to the first dose; active infection withconcurrent treatment is acceptable only if the patient is clinically stable

• Significantly diseased (as determined by the principal investigator [PI] or treatingphysician) or obstructed gastrointestinal tract or uncontrolled vomiting or diarrhea

• Treatment with an investigational anti-cancer study drug within 3 weeks prior tostudy drug administration date

• Concurrent therapy with approved or investigational anticancer therapeutics

• Medical, psychological or social conditions that may interfere with the patient'sparticipation in the study or evaluation of the study results

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

• For Arms L (pembrolizumab) and M (nivolumab), and Arms N, O, P (nivolumab andipilimumab), subjects with an active, known or suspected autoimmune disease;subjects with type I diabetes mellitus, hypothyroidism only requiring hormonereplacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiringsystemic treatment, or conditions not expected to recur in the absence of anexternal trigger are permitted to enroll

• For Arms L (pembrolizumab) and M (nivolumab), and Arms N, O, P (nivolumab andipilimumab), subjects receiving chronic systemic steroid therapy (in dosingexceeding 10 mg daily of prednisone equivalent) or other form of immunosuppressivetherapy within 7 days before the first dose of study treatment; use of inhaled ortopical steroids or systemic corticosteroids =< 10 mg is permitted; in addition,physiologic steroid replacement with hydrocortisone is allowed

• For Arms L (pembrolizumab) and M (nivolumab), and Arms N, O, P (nivolumab andipilimumab), history of a prior grade 3 or 4 immune-related adverse event (irAE) orany grade ocular irAE from prior immunotherapy

• For the Arm O (nivolumab and ipilimumab) expansion Cohort O-2, patients must nothave melanoma, RCC, or NSCLC