A Study of Selinexor in People With Wilms Tumors and Other Solid Tumors

A Multi-Center Phase II Study of Selinexor in Treating Recurrent or Refractory Wilms Tumor and Other Pediatric Solid Tumors

The purpose of this study is to find out whether selinexor is an effective treatment for people under the age of 51 who have a relapsed/refractory Wilms tumor, rhabdoid tumor, MPNST, or another solid tumor that makes a higher than normal amount of XPO1 or has genetic changes that increase the activity of XP01.

Study Overview

• Status: Recruiting
• Conditions: Solid Tumor; Rhabdoid Tumor; Wilms Tumor; Nephroblastoma; Malignant Peripheral Nerve Sheath Tumors; MPNST; XPO1 Gene Mutation
• Intervention / Treatment: Drug: Selinexor

• Study Type: Interventional
• Enrollment (Estimated): 36
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Michael Ortiz, MD; Phone Number: 1-833-MSK-KIDS; Email: ortizm2@mskcc.org
• Study Contact Backup: Name: Julia Glade Bender, MD; Phone Number: 1-833-MSK-KIDS

Study Locations

• United States
  • California
    • Los Angeles, California, United States, 90027
      • Not yet recruiting
      • Children's Hospital of Los Angeles (Data Collection Only)
      • Contact: Rachana Shah, MD; Phone Number: 323-660-2450
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Not yet recruiting
      • Children's Healthcare of Atlanta (Data Collection and Specimen Analysis)
      • Contact: Thomas Cash, MD; Phone Number: 404-785-0910
  • Massachusetts
    • Boston, Massachusetts, United States, 02115
      • Not yet recruiting
      • Dana Farber Cancer Institute (Data Collection Only)
      • Contact: Elizabeth Mullen, MD; Phone Number: 617-632-1938
  • New Jersey
    • Basking Ridge, New Jersey, United States, 07920
      • Recruiting
      • Memorial Sloan Kettering at Basking Ridge (Limited Protocol Activities)
      • Contact: Michael Ortiz, MD; Phone Number: 833-675-5437
    • Middletown, New Jersey, United States, 07748
      • Recruiting
      • Memorial Sloan Kettering Monmouth (Limited Protocol Activities)
      • Contact: Michael Ortiz, MD; Phone Number: 833-675-5437
    • Montvale, New Jersey, United States, 07645
      • Recruiting
      • Memorial Sloan Kettering Bergen (Limited Protocol Activities)
      • Contact: Michael Ortiz, MD; Phone Number: 833-675-5437
  • New York
    • Commack, New York, United States, 11725
      • Recruiting
      • Memorial Sloan Kettering Suffolk-Commack (Limited Protocol Activities )
      • Contact: Michael Ortiz, MD; Phone Number: 833-675-5437
    • Harrison, New York, United States, 10604
      • Recruiting
      • Memorial Sloan Kettering Westchester (Limited Protocol Activities)
      • Contact: Michael Ortiz, MD; Phone Number: 833-675-5437
    • New York, New York, United States, 10065
      • Recruiting
      • Memorial Sloan Kettering Cancer Center (All protocol activites)
      • Contact: Michael Ortiz, MD; Phone Number: 833-675-5437
    • Rockville Centre, New York, United States, 11553
      • Recruiting
      • Memorial Sloan Kettering Nassau (Limited Protocol Activities)
      • Contact: Michael Ortiz, MD; Phone Number: 833-675-5437
  • Ohio
    • Cincinnati, Ohio, United States, 45229
      • Not yet recruiting
      • Cincinnati Children's Hospital Medical Center (Data Collection Only)
      • Contact: James Geller, MD; Phone Number: 513-517-2234

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Child; Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age:

  1. Age ≥ 6 at the time of informed consent
  2. Age ≥ 2 years to < 6 years at time of informed consent (Refer to Section 4.3): If PK cohort 1 is open, patients in this age range may enroll onto this cohort. If PK cohort 1 has been completed and deemed sufficient to proceed, then such patients may enroll onto the phase 2.
  3. Age ≥ 12 months to < 2 years at time of informed consent (Refer to Section 4.3):

If PK cohort 2 is open, patients in this age range may enroll onto this cohort. If PK cohort 2 has been completed and deemed sufficient to proceed, then such patients may enroll onto the phase 2.

• Consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
• Performance: Karnofsky ≥ 60% for patients > 16 years of age and Lansky ≥ 60 for patients ≤ 16 years of age.

• Diagnosis: Patients must enroll into one of the following cohorts:

  1. Cohort A: Any type of Wilms tumor or nephroblastoma is eligible for this study provided they meet at least one of these criteria: (1) in their second or greater relapse, (2) refractory or in their first relapse with high risk histology (i.e., any anaplastic or blastemal-type after neoadjuvant chemotherapy), or (3) refractory or in first relapse without high risk histology but after having received chemotherapies other than the initial 4 agents used as current standard of care in the up-front setting for non-high risk cases - specifically vincristine, dactinomycin, doxorubicin, and irinotecan (i.e., any patient who relapses following an initial regimen more intense than EE4A, DD4A, VAD, AVD, or VIVA; for example, those including cyclophosphamide/etoposide - such as Regimen I, M, or MVI - or those additionally including carboplatin - such as Regimens UH-1, UH-2, or UH-3).

  2. Cohort B: Any Rhabdoid tumor is eligible for this cohort. This includes, but is not limited to, related subtypes of rhabdoid tumors such as atypical teratoid rhabdoid tumors (ATRT), malignant rhabdoid tumors of the kidney (MRTK), malignant rhabdoid tumors of the soft tissue and liver, small cell undifferentiated hepatoblastomas (SCUH), and small-cell carcinoma of the ovary of hypercalcemic type (SCCOHT). Patients must have failed to respond to at least

     1 line of systemic therapy prior to enrollment.

  3. Cohort C: Patients with progressive, relapsed, unresectable or metastatic MPNST, are eligible for this cohort. Patients must have failed to respond to at least 1 line of systemic therapy prior to enrollment.
  4. Cohort D: Patients must not qualify for Cohorts A, B, or C but have a solid tumor (no hematologic malignancies including lymphoma) for which there is specific evidence that this particular patient's tumor may benefit from selinexor.

Patients must have failed to respond to at least 1 line of systemic therapy prior to enrollment. Examples of evidence are listed below. All patients in this cohort require approval of study principal investigator and must provide documentation of specific supporting evidence. i. Tumor XPO1 Dependency: Defined as either Darwin OncoTarget demonstrating XPO1 as aberrantly activated or Darwin OncoTreat demonstrating context-specific tumor checkpoint inversion with Selinexor, both of which must be significant at a -log10 (Bonferroni corrected p-value) of 5 or greater. ii. Tumor XPO1 Activation: Defined as the detection of a gain of function mutation in XPO1, specifically E571K. Additionally, detection of elevated transcriptomic or proteomic expression of XPO1 in the tumor via RNAseq or IHC, respectively, would be considered sufficient for treatment. iii. Preclinical Tumor Testing: Defined as testing of Selinexor on patient derived cell line, organoid, or xenograft models of the patient's tumor (or other related tumors) performed in a laboratory context and for which, in the investigator's opinion, demonstrates promising activity. Testing may include commercial testing as well as academic laboratory testing.

• Disease Status: Patients on the phase II portion of the study must have measurable disease whereas patients on the PK cohorts can have either evaluable or measurable disease as measured by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline (Version 1.1).

  a. Primary Brain Tumors: Patients with primary brain tumors are eligible and must also have measurable disease for the phase II (as well as evaluable or measurable for the PK cohorts), but this can be defined as at least equal or greater than twice the slice thickness in two perpendicular diameters on MRI OR diffuse leptomeningeal disease OR clear MRI evidence of disease that may not be measurable in two perpendicular diameters OR positive CSF cytology alone.

• Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and meet minimum washout durations (shown below) from prior therapy.

  1. Anti-cancer agents not known to be myelosuppressive: ≥ 7 days
  2. Anti-cancer and cytotoxic agents known to be myelosuppressive: ≥ 21 days
  3. Immunotherapies (including antibodies, interleukins, interferons, etc.): ≥ 21 days
  4. Adoptive cellular therapies (including modified T cells, vaccines, etc.): ≥ 42 days
  5. Autologous stem cell infusion (boost, no conditioning): ≥ 21 days
  6. Autologous stem cell transplantation (with conditioning): ≥ 42 days
  7. Allogeneic bone marrow transplantation: ≥ 84 days
  8. Focal external beam radiation (e.g., limited sites of disease): ≥ 14 days
  9. Substantial external beam radiation (e.g. whole lung or abdomen): ≥ 42 days
  10. Radiopharmaceutical therapy (e.g., radiolabeled antibody or MIBG): ≥ 42 days

• Hepatic Function: Adequate function (within 14 days prior to C1D1), defined as:

  1. Total bilirubin < 1.5 × upper limit of normal (ULN) (except patients with Gilbert's syndrome, who must have a total bilirubin of <3 × ULN)
  2. Alanine aminotransferase (ALT) < 3 × ULN
  3. Serum albumin ≥ 2 g/dL

• Renal Function: Adequate function (within 14 days prior to C1D1) defined as a GFR

  ≥ 50 ml/min/1.73 m2 determined via any of these methods:

  1. Nuclear radioisotope
  2. 24 hr urine creatinine clearance
  3. Serum cystatin c
  4. Serum creatinine using the Schwartz formula for estimating creatinine clearance (Schwartz et al. J Peds, 106:522, 1985)

• Hematologic Function: Adequate function (within 14 days prior to C1D1), defined as:

  1. Absolute neutrophil count (ANC) ≥ 1000/mm3
  2. Platelet count ≥ 100,000/mm3
  3. Note: patients may not receive platelet transfusions nor hematopoietic growth factor support, including granulocyte-colony stimulating factor (e.g. filgrastim) and platelet stimulators (e.g. romiplostim) for at least 7 days prior to demonstrating adequate hematologic function.

Exclusion Criteria:

• Prior Therapy: Has received selinexor or another XPO1 inhibitor previously.
• Infection: Patients who have an uncontrolled infection are not eligible. Patients on prophylactic antibiotics or with a controlled infection within 1 week prior to C1D1 are acceptable
• Transplants: Patients who have received allogeneic bone marrow transplant are potentially eligible unless they are being actively treated for GvHD. Patients who have had a prior solid organ transplantation are not eligible.
• Compliance: Patients who as a result of serious medical, psychiatric, and/or social situation(s), in the opinion of the investigator, may not be able to comply with supportive care, safety monitoring, or any other key requirements of the study protocols are not eligible.
• Pregnancy and Breast-feeding: Pregnant or breast-feeding women will not be entered on this study because there is yet no available information regarding human fetal or teratogenic toxicities. Pregnancy tests must be obtained in girls who are post-menarchal.
• Contraception: Males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (e.g., male or female condom) for the duration of the study. Abstinence is an acceptable method of birth control.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort A.1 Wilms Tumor; Participants will have any type of Wilms tumor or nephroblastoma	Drug: Selinexor; This phase II study will initially treat all patients, including adult patients, at the pediatric Selinexor RP2D of 35 mg/m2 (no maximum dose) once weekly using a liquid suspension .
Experimental: Cohort B.1 Rhabdoid Tumor; Participants will have any Rhabdoid tumor	Drug: Selinexor; This phase II study will initially treat all patients, including adult patients, at the pediatric Selinexor RP2D of 35 mg/m2 (no maximum dose) once weekly using a liquid suspension .
Experimental: Cohort C.1 MPNST; Participants will have progressive, relapsed, unresectable or metastatic MPNST	Drug: Selinexor; This phase II study will initially treat all patients, including adult patients, at the pediatric Selinexor RP2D of 35 mg/m2 (no maximum dose) once weekly using a liquid suspension .
Experimental: Cohort D.1 Other Solid Tumor; Participants must not qualify for Cohorts A, B, or C but have a solid tumor (no hematologic malignancies including lymphoma) for which there is specific evidence that this particular patient's tumor may benefit from selinexor.	Drug: Selinexor; This phase II study will initially treat all patients, including adult patients, at the pediatric Selinexor RP2D of 35 mg/m2 (no maximum dose) once weekly using a liquid suspension .

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Response Rate	To define the antitumor activity of Selinexor in relapsed and refractory Wilms tumor by measuring the Overall Response Rate, defined as Complete Response + Partical Response	1 year

Collaborators and Investigators

• Sponsor: Memorial Sloan Kettering Cancer Center
• Investigators: Principal Investigator: Michael Ortiz, MD, Memorial Sloan Kettering Cancer Center

Publications and helpful links

Helpful Links

• Memorial Sloan Kettering Cancer Center

Study record dates

Study Major Dates

• Study Start (Actual): August 1, 2023
• Primary Completion (Estimated): August 1, 2029
• Study Completion (Estimated): August 1, 2029

Study Registration Dates

• First Submitted: August 2, 2023
• First Submitted That Met QC Criteria: August 2, 2023
• First Posted (Actual): August 14, 2023

Study Record Updates

• Last Update Posted (Actual): August 14, 2023
• Last Update Submitted That Met QC Criteria: August 2, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Keywords: Memorial Sloan Kettering Cancer Center; Solid Tumor; MPNST; Selinexor; Malignant Peripheral Nerve Sheath Tumors; Wilms Tumor; Rhabdoid Tumor; Nephroblastoma; XPO1; 22-393
• Additional Relevant MeSH Terms: Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Kidney Diseases; Urologic Diseases; Genetic Diseases, Inborn; Neuromuscular Diseases; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Kidney Neoplasms; Nervous System Neoplasms; Neoplastic Syndromes, Hereditary; Neoplasms, Complex and Mixed; Neoplasms, Connective Tissue; Sarcoma; Peripheral Nervous System Neoplasms; Neoplasms, Fibrous Tissue; Fibrosarcoma; Neurofibroma; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Neoplasms; Rhabdoid Tumor; Nerve Sheath Neoplasms; Wilms Tumor; Neurofibrosarcoma
• Other Study ID Numbers: 22-393

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: • Memorial Sloan Kettering Cancer Center supports the international committee of medical journal editors (ICMJE) and the ethical obligation of responsible sharing of data from clinical trials. The protocol summary, a statistical summary, and informed consent form will be made available on clinicaltrials.gov when required as a condition of Federal awards, other agreements supporting the research and/or as otherwise required. Requests for deidentified individual participant data can be made beginning 12 months after publication and for up to 36 months post publication. Deidentified individual participant data reported in the manuscript will be shared under the terms of a Data Use Agreement and may only be used for approved proposals. Requests may be made to: crdatashare@mskcc.org.

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No