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

Study Overview
=================
Brief Summary
-----------------
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.

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

Conditions
-----------------
Wilms Tumor, Rhabdoid Tumor, MPNST, Malignant Peripheral Nerve Sheath Tumors, Nephroblastoma, XPO1 Gene Mutation, Solid Tumor

Intervention / Treatment
-----------------
* Drug: Selinexor


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Age: Age ≥ 6 at the time of informed consent 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. 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: 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). 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. 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. 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. Anti-cancer agents not known to be myelosuppressive: ≥ 7 days Anti-cancer and cytotoxic agents known to be myelosuppressive: ≥ 21 days Immunotherapies (including antibodies, interleukins, interferons, etc.): ≥ 21 days Adoptive cellular therapies (including modified T cells, vaccines, etc.): ≥ 42 days Autologous stem cell infusion (boost, no conditioning): ≥ 21 days Autologous stem cell transplantation (with conditioning): ≥ 42 days Allogeneic bone marrow transplantation: ≥ 84 days Focal external beam radiation (e.g., limited sites of disease): ≥ 14 days Substantial external beam radiation (e.g. whole lung or abdomen): ≥ 42 days Radiopharmaceutical therapy (e.g., radiolabeled antibody or MIBG): ≥ 42 days Hepatic Function: Adequate function (within 14 days prior to C1D1), defined as: Total bilirubin < 1.5 × upper limit of normal (ULN) (except patients with Gilbert's syndrome, who must have a total bilirubin of <3 × ULN) Alanine aminotransferase (ALT) < 3 × ULN 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: Nuclear radioisotope 24 hr urine creatinine clearance Serum cystatin c 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: Absolute neutrophil count (ANC) ≥ 1000/mm3 Platelet count ≥ 100,000/mm3 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.

Ages Eligible for Study
-----------------
Minimum Age: 12 Months

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cohort A.1 Wilms Tumor<br>Participants will have any type of Wilms tumor or nephroblastoma | Drug: Selinexor<br>* 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 .<br>|
| Experimental: Cohort B.1 Rhabdoid Tumor<br>Participants will have any Rhabdoid tumor | Drug: Selinexor<br>* 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 .<br>|
| Experimental: Cohort C.1 MPNST<br>Participants will have progressive, relapsed, unresectable or metastatic MPNST | Drug: Selinexor<br>* 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 .<br>|
| Experimental: Cohort D.1 Other Solid Tumor<br>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<br>* 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 .<br>|

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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Wilms Tumor, Rhabdoid Tumor, Malignant Peripheral Nerve Sheath Tumors, MPNST, Nephroblastoma, XPO1, Selinexor, Memorial Sloan Kettering Cancer Center, 22-393, Solid Tumor