Study of the Safety, Tolerability and Efficacy of KPT-8602 in Participants With Relapsed/Refractory Cancer Indications

• Status: Recruiting
• Trial end date: 2024-08-31
• Target enrollment: 0
• Participant gender: All

Summary

This is a first-in-human, multi-center, open-label clinical study with separate dose escalation (Phase 1) and expansion (Phase 2) stages to assess preliminary safety, tolerability, and efficacy of the second generation oral XPO1 inhibitor KPT-8602 in participants with relapsed/refractory multiple myeloma (MM), metastatic colorectal cancer (mCRC), metastatic castration resistant prostate cancer (mCRPC), and higher risk myelodysplastic syndrome (HR-MDS).

Dose escalation and dose expansion may be included for all parts of the study as determined by ongoing study results.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: Karyopharm Therapeutics Inc; Karyopharm Therapeutics, Inc
• Treatments: Dexamethasone

Criteria

INCLUSION CRITERIA

1. Written informed consent obtained prior to any screening procedures and in accordance with federal, local, and institutional guidelines.

2. Age ≥ 18 years.

INDICATION-SPECIFIC INCLUSION CRITERIA

Relapsed/Refractory Multiple Myeloma (Parts A1, A2, and B):

3. Symptomatic, histologically confirmed multiple myeloma (MM) and evidence of disease progression, based on International Myeloma Working Group (IMWG) guidelines.

4. Participants receiving hematopoietic growth factor support including erythropoietin, darbepoetin, granulocyte-colony stimulating factor, granulocyte macrophage-colony stimulating factor, and platelet stimulators can continue to do so, but must be transfusion independent for at least 1 week prior to Cycle 1 Day 1 (C1D1) in the study.

Relapsed/Refractory Colorectal Cancer (Part C):

5. Histological or cytological documentation of adenocarcinoma of the colon or rectum.

6. Documented evidence of progressive disease according to Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1.

Relapsed/Refractory Metastatic Castration-resistant Prostate Cancer (Parts D and E):

7. Histologically confirmed adenocarcinoma of the prostate with archival tumor tissue available for molecular analyses. If the participants does not have a prior histological diagnosis, then a fresh biopsy at screening may be used for this purpose.

8. Participants should not be transfusion dependent.

9. Part E only: Participants currently receiving treatment with abiraterone and appropriate to continue in the opinion of the Investigator. Participants must also have been on and continue on a stable dose of corticosteroids (prednisone or dexamethasone) for 30 days prior to C1D1.

Higher Risk Myelodysplastic Syndrome (Part F):

10. Documented diagnosis of MDS with 5-19% myeloblasts.

11. Participants should be intermediate-2 or high-risk MDS by International Prognostic Scoring System (IPSS).

12. Participants believed to be IPSS high risk, without clearly meeting IPSS categories above should be discussed with the medical monitor prior to enrolling.

13. Hypomethylating agents (HMA) refractory participants including:

1. ≥ 2 cycles of azacitidine and/or decitabine or experimental agents (such as SGI-110 or ASTX727 or similar) with clear progressive disease (PD) (no count recovery with ≥50% increase in bone marrow blasts) OR

2. ≥ 4 cycles of azacitidine and/or decitabine (or other hypomethylating therapy) with lack of improvement (no CR/CRi/PR/HI).

14. Participants receiving a stable dose of erythropoiesis-stimulating agent (ESA) for at least 1 month at the time of study entry may continue to receive ESA.

15. Participants in Part F Phase 2 with RR high-risk myelodysplastic Syndrome should have documented diagnosis of MDS with 5 to 19 percentage myeloblasts in the bone marrow.

16. Participants in Part G with Newly Diagnosed Intermediate/ High-risk Myelodysplastic Syndrome should have diagnosis of MDS with 5 to 19 percentage myeloblasts in the bone marrow.

EXCLUSION CRITERIA

Participants in All Parts of the Study:

1. Major surgery within 4 weeks before C1D1.

2. Impaired cardiac function or clinically significant cardiac diseases.

3. Uncontrolled active severe systemic infection requiring parenteral antibiotics, antivirals, or antifungals within one week prior to C1D1.

4. Participants with known symptomatic brain metastasis.

5. Prior malignancies:

1. Participants in All Parts of the Study: Participants with adequately resected basal or squamous cell carcinoma of the skin, or adequately resected carcinoma in situ (i.e. cervix) may enroll irrespective of the time of diagnosis.

2. Participants with Higher Risk MDS only: Concomitant malignancies or previous malignancies with less than a 1-year disease free interval at the time of enrollment.

6. Participants with gastrointestinal tract disease (or uncontrolled vomiting or diarrhea) that could interfere with the absorption of eltanexor (or ASTX727 in Part G).

INDICATION-SPECIFIC EXCLUSION CRITERIA

Relapsed/Refractory Multiple Myeloma (RRMM) (Parts A1, A2 and B):

7. Time since the last prior therapy for treatment of RRMM:

1. Radiation, chemotherapy, immunotherapy or any other anticancer therapy, including investigational anticancer therapy <=2 weeks prior to C1D1.

2. Palliative steroids for disease related symptoms are allowed up to 3 days prior to C1D1.

3. Participants must have recovered or stabilized (<=Grade 1 or to their baseline) from toxicities related to their previous treatment except for alopecia.

8. Participants with active graft versus host disease after allogeneic stem cell transplantation. At least 3 months must have elapsed since completion of allogeneic stem cell transplantation.

9. Grade >2 peripheral neuropathy or Grade 2 peripheral neuropathy with pain within 2 weeks prior to C1D1.

Relapsed/Refractory Colorectal Cancer (Part C):

10. Radiotherapy, chemotherapy, or any other anticancer therapy, including investigational anticancer therapy within 2 weeks prior to Screening. Participants must have recovered from clinically significant toxicities. The site of irradiation should have evidence of progressive disease (new lesions or increase in lesion size) if this is the only site of disease.

11. Participants who have been treated with their most recent chemotherapy or investigational drugs <=21 days or 5 half-lives (whichever is longer) prior to the first dose of study treatment, and/or have any acute toxicities due to prior chemotherapy and/ or radiotherapy that have not resolved to a National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03 Grade 0 or Grade 1 with the exception of chemotherapy induced alopecia and Grade 2 peripheral neuropathy.

Relapsed/Refractory Metastatic Castration-Resistant Prostate Cancer (Parts D and E):

12. Participants who have been treated with their most recent chemotherapy or investigational drugs <=21 days or 5 half-lives (whichever is longer) prior to the first dose of study treatment, and/or have any acute toxicities due to prior chemotherapy and/ or radiotherapy that have not resolved to a NCI CTCAE v4.03 Grade 0 or Grade 1 with the exception of chemotherapy induced alopecia and Grade 2 peripheral neuropathy.

13. Initiating bisphosphonate therapy or adjusting bisphosphonate dose/regimen within 30 days prior to C1D1. Participants on a stable bisphosphonate or denosumab regimen are eligible and may continue.

Higher risk Myelodysplastic Syndrome (Part F Phase 2 and Part G):

14. IPSS very low or low-1 risk MDS.

15. Evidence of transformation to AML by World Health Organization (WHO) (≥20% blasts in bone marrow or peripheral blood).

16. Participants receiving granulocyte-colony stimulating factor (G-CSF) or granulocyte macrophage-colony stimulating factor (GM-CSF) within the 3 weeks prior to C1D1.