Bioequivalence and the Tolerability and Antitumor Activity of Selinexor Combination Treatment

Key Inclusion Criteria:

Patients are eligible to be included in the study only if they meet all of the following criteria:

1. Are ≥18 years of age.

2. Have histologically confirmed advanced or metastatic NSCLC or CRC (patients with either KRAS mutation or wild type are eligible; however, at least 10 patients with CRC must have KRAS-mutant disease).

3. Patients must have evidence of measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST v1.1).

4. Have received prior therapy as follows:

1. For patients with NSCLC, have received at least 1 but no more than 2 prior line(s) of systemic anti-cancer treatment with 1 regimen including a checkpoint inhibitor (CPI).

2. For patients with CRC, have received 2 prior lines of systemic anti-cancer treatment (oxaliplatin- and irinotecan-based); no prior therapy with immunotherapy.

5. Female patients of childbearing potential must have a negative serum pregnancy test at screening and agree to use highly effective (dual methods of) contraception throughout the study and for 1 week following the last dose of study drug; and male patients must use an effective barrier method of contraception throughout the study and for 1 week following the last dose of study drug if sexually active with a female of childbearing potential.

6. Willing to provide written informed consent in accordance with federal, local, and institutional guidelines and comply with all requirements of the trial.

Key Exclusion Criteria:

Patients are excluded from the study if any of the following criteria apply:

1. Have an Eastern Cooperative Oncology Group (ECOG) performance status of ≥2.

2. Have a life expectancy of <12 weeks, as determined by the Investigator.

3. Have inadequate hepatic function defined as total bilirubin, aspartate aminotransferase (AST), or alanine aminotransferase (ALT) > upper limit of normal (ULN). Patients with mild hepatic dysfunction (total bilirubin of 1 - 1.5 × ULN or AST/ALT of 1 - 2 × ULN) may be included in the study if approved by the Sponsor's Medical Monitor.

4. Have inadequate hematopoietic function defined as absolute neutrophil count (ANC) <1.5 × 10⁹/L; platelet count (PLT) <100 × 10⁹/L; or hemoglobin (Hb) <9 g/dL.

5. Had transfusions or hematopoietic growth factors <7 days of Day 1 dosing.

6. Have inadequate renal function defined as a calculated creatinine clearance (CrCl) of <20 mL/min using the formula of Cockcroft and Gault.

7. Have any other medical condition especially any gastrointestinal (GI) dysfunctions or GI disease that could interfere with the absorption of selinexor (e.g., inability to swallow tablets, malabsorption syndrome, a history of GI surgery which may result in intestinal blind loop, significant gastroparesis, unresolved nausea, vomiting, or diarrhea [National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Grade >1]) or have any general inability to swallow and retain oral medications.

8. Unstable cardiovascular function:

1. symptomatic ischemia, or

2. congestive heart failure of New York Heart Association Class ≥3, or

3. myocardial infarction within 3 months of Day 1 dosing.

9. Received strong cytochrome P450 3A (CYP3A) inhibitors OR strong CYP3A inducers ≤7 days prior to Day 1 dosing.

10. Ongoing infection requiring parenteral antibiotics, antivirals, or antifungals on Day 1 dosing.

11. Insufficient time since or not recovered from procedures or anti-cancer therapy, defined as:

1. Not recovered from major surgery ≤21 days prior to Day 1 dosing. Minor procedures, such as biopsies, dental work, or placement of a port or intravenous line for infusion are permitted.

2. Have ongoing clinically significant anti-cancer therapy-related toxicities CTCAE Grade >1. In specific cases, patients whose toxicity has stabilized or with Grade 2 non-hematologic toxicities can be allowed following documented approval by the Sponsor's Medical Monitor.

3. Had last dose of previous anti-cancer therapy ≤14 days prior to Day 1 dosing.

12. Inability or unwillingness to undergo a series of PK sampling.

13. Inability or unwillingness to take supportive medications such as anti-nausea and anti-anorexia agents as recommended by the NCCN Clinical Practice Guidelines in Oncology for antiemesis and anorexia/cachexia (palliative care).

14. Serious psychiatric or medical conditions that could interfere with participation in the study or in the opinion of the Investigator would make study involvement unreasonably hazardous.

15. In the opinion of the Investigator, patients who are significantly below their ideal body weight.

16. Known allergy to selinexor (all patients), docetaxel (NSCLC Cohort only), or pembrolizumab (CRC Cohort only).

17. Female patients who are pregnant or lactating.

18. Patients with CRC who are to receive pembrolizumab:

1. had a diagnosis of immunodeficiency or are receiving systemic steroid therapy (>10 mg/day of prednisone or equivalent) or any other form of immunosuppressive therapy.

2. are diagnosed with endocrinopathies, such as abnormal thyroid function. Patients on stable hormone replacement therapy are allowed.

3. have active autoimmune disease requiring systemic treatment during the past 2 years. Type 1 diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted.

The following exclusion criteria define patients to be excluded from the Combination Therapy Period upon completion of the Monotherapy Period:

19. Have PLT <100 × 10⁹/L, ANC <1.0 × 10⁹/L (for patients with NSCLC who are to receive docetaxel, ANC <1.5 × 10⁹/L), or Hb <9 g/dL.

20. Have an ECOG performance status of ≥3.

21. Have not recovered or stabilized from nonhematologic toxicities related to selinexor, with recovery defined as Grade 1 or baseline for nonhematologic AEs. Patients with certain Grade 2 nonhematologic toxicities can be allowed following approval by the Sponsor's Medical Monitor.

Note: Dose interruption between the Monotherapy Period and the Combination Therapy Period is allowed for recovery from AEs. Patients requiring >21 days after the End of Monotherapy Treatment visit to recover from toxicities related to selinexor should be discussed with the Sponsor's Medical Monitor for approval to continue to the Combination Therapy Period.

22. For patients with CRC who are to receive pembrolizumab, have received live-attenuated vaccine against an infectious disease (e.g., influenza) ≤14 days prior to Cycle 1 Day 1 (C1D1).

23. For patients with NSCLC who are to receive docetaxel, have a bilirubin >ULN or AST and/or ALT >1.5 × ULN concurrent with alkaline phosphatase >2.5 × ULN.