Silmitasertib (CX-4945) in Combination With Chemotherapy for Relapsed Refractory Solid Tumors

Phase 1

Recruiting

• Conditions: Neuroblastoma Recurrent; Liposarcoma Recurrent; Ewing's Sarcoma Recurrent; Osteosarcoma Recurrent; Rhabdomyosarcoma Recurrent
• Interventions: Drug: Silmitasertib; Drug: Irinotecan; Drug: Temozolomide; Drug: Vincristine

• Registration Number: NCT06541262
• Lead Sponsor: Milton S. Hershey Medical Center

Brief Summary

The purpose of this study is to evaluate the investigational drug, silmitasertib (a pill taken by mouth), in combination with FDA approved drugs for solid tumors. An investigational drug is one that has not been approved by the U.S. Food \& Drug Administration (FDA), or any other regulatory authorities around the world for use alone or in combination with an...

Detailed Description

Not available

Basic Information
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Recruitment & Eligibility
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Study & Design
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Trial Locations
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Study Timeline

• Study First Submitted: 2024-08-02
• Study First Submitted QC: 2024-08-02
• Study First Posted: 2024-08-07
• Status Verified: 2024-10
• Study Start: 2024-10-30
• Last Update Submitted: 2024-10-30
• Last Update Posted: 2024-11-01
• Primary Completion: 2030-11-01
• Study Completion: 2035-11-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 114

Inclusion Criteria

1. Age: Less than 30 years old at initial diagnosis

2. Pathology All subjects must have a confirmed diagnosis of tumor type. Phase I: Relapsed/refractory solid tumors: Neuroblastoma, Ewing Sarcoma, Osteosarcoma, Rhabdomyosarcoma, Liposarcoma

   Phase II:

   • Relapsed/refractory Neuroblastoma
   • Relapsed/refractory Ewing sarcoma

3. Tumor assessment:

   Disease assessment is required for eligibility and must be done after last dose of previous therapy and prior to first dose of study drug.

4. Disease Status:

   Relapsed/Refractory Neuroblastoma Relapsed disease defined as neuroblastoma that was previously in remission after standard therapy (at least 4 cycles of aggressive multi-drug induction chemotherapy, with or without radiation and surgery, followed by immunotherapy, or according to a standard high-risk treatment/neuroblastoma protocol) and has now relapsed and is in any number of relapses.

   Refractory disease defined as High-risk neuroblastoma (as defined by INRG) that failed to achieve CR after at least 4 cycles of aggressive multi-drug induction chemotherapy, progression during upfront therapy or with disease remaining after standard immunotherapy.

   International Neuroblastoma Risk Group Staging System (INRG) High Risk NB defined as one of the following:

   1. Any age with International Neuroblastoma Risk Group (INRG) Stage L2, MS, or M with MYCN amplification
   2. Age ≥ 547 days and INRG Stage M regardless of biologic features
   3. Any age initially diagnosed with INRG Stage L1 MYCN amplified NBL who have progressed to Stage M without systemic chemotherapy
   4. Age ≥ 547 days of age initially diagnosed with INRG Stage L1, L2, or MS who have progressed to Stage M without systemic chemotherapy

   Relapsed/refractory Sarcoma Subjects that have relapsed following standard of care therapy or having progressed during standard of care therapy. Standard of care therapy for sarcoma includes multi-agent chemotherapy with local control consisting of either surgery or radiation therapy.

5. Measurable or evaluable disease, including at least one of the following:

   • Measurable tumor by CT or MRI
   • MIBG or PET that is positive for disease
   • Bone Marrow biopsy/aspirate that is positive for disease

6. Timing from prior therapy:

   Subjects must have fully recovered from the acute toxic effects of all prior anti- cancer therapy and be within the following timelines:

   1. Myelosuppressive chemotherapy: Must not have received within 2 weeks of enrollment onto this study.

   2. Small Molecule Inhibitors (anti-neoplastic agent): At least 2 weeks from the completion of therapy with a small molecule inhibitor.

   3. Immunotherapy: At least 4 weeks since the completion of any type of immunotherapy, e.g. tumor vaccines, CAR-T cells, anti-GD2 Monoclonal antibodies (ex. naxitamab, dinutuximab, etc.).

   4. Radiotherapy: At least 30 days since the last treatment except for radiation delivered with palliative intent to a non-target site.

   5. Stem Cell Transplant:

      • Allogeneic: No evidence of active graft vs. host disease
      • Allogeneic/Autologous: ≥ 2 months must have elapsed since transplant.

   6. MIBG Therapy: At least 6 weeks since treatment with MIBG therapy.

7. Subjects must have a Lansky or Karnofsky Performance Scale score of >/= 50.

8. Subject must be able to swallow capsules.

9. Subjects must have adequate organ function at the time of enrollment:

   • Cardiac- Corrected QT (QTc) interval <480ms (calculated using Bazett formula)
   • Hematological: Hematological recovery as defined by ANC ≥750/μL
   • Liver: Adequate liver function as defined by AST and ALT <5x upper limit of normal
   • Renal: Subjects must have adequate renal function defined as Creatinine clearance (in units ml/min) or radioisotope GFR ≥ 70.

   The formula to be used: Adjusted GFR=(Estimated GFR×BSA/ 1.73) mL/min

10. Subjects of childbearing potential must have a negative serum pregnancy test. Subjects of childbearing potential must agree to use effective measures to avoid pregnancy.

11. Written informed consent in accordance with institutional and FDA guidelines must be obtained from all subjects (or subjects' legal representative).

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Exclusion Criteria

1. Investigational Drugs: Subjects who are currently receiving another investigational drug are excluded from participation.

2. Anti-cancer Agents: Subjects who are currently receiving other anticancer agents are not eligible. Subjects must have fully recovered from the hematological and bone marrow suppression effects of prior therapy.

3. Subjects who are currently receiving Vitamin K antagonists (warfarin).

4. Subjects who are currently receiving the class of lipid-lowering medications HMG-CoA reductase inhibitors (statins).

5. Infection: Subjects who have an uncontrolled infection are not eligible until the infection is judged to be well controlled in the opinion of the investigator.

6. Subjects who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study, or in whom compliance is likely to be suboptimal, should be excluded.

7. Subjects with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that in the opinion of the investigator would compromise the subject's ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results.

8. Subjects with any of the following gastrointestinal disorders:

   1. Difficulty with swallowing or active malabsorption (e.g. short gut) syndrome.
   2. Uncontrolled diarrhea (excess of 4 stools/day)
   3. Gastritis, ulcerative colitis, Chron's disease or hemorrhagic coloproctitis
   4. History of gastric or small bowel surgery involving any extent of gastric or small bowel resection

9. Lactating subjects are not eligible unless they have agreed to not breastfeed their infants. There is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the nursing subject with silmitasertib. (NOTE: breast milk cannot be stored for future use while the nursing subject is being treated on study.)

10. Subjects with a history of any other malignancy.

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Phase I- Dose level 2	Irinotecan	Silmitasertib 800 mg/m2 twice a day plus Neuroblastoma: Regimen A: Irinotecan and Temozolomide Sarcoma: Regimen B: Vincristine, Irinotecan and Temozolomide
Phase I- Dose level 2	Silmitasertib	Silmitasertib 800 mg/m2 twice a day plus Neuroblastoma: Regimen A: Irinotecan and Temozolomide Sarcoma: Regimen B: Vincristine, Irinotecan and Temozolomide
Phase II- Relapsed/refractory Neuroblastoma	Irinotecan	Silmitasertib RP2D twice a day plus Irinotecan and Temozolomide
Phase I- Dose level 1	Vincristine	Silmitasertib 600 mg/m2 twice a day plus Neuroblastoma: Regimen A: Irinotecan and Temozolomide Sarcoma: Regimen B: Vincristine, Irinotecan and Temozolomide
Phase I- Dose level 1	Silmitasertib	Silmitasertib 600 mg/m2 twice a day plus Neuroblastoma: Regimen A: Irinotecan and Temozolomide Sarcoma: Regimen B: Vincristine, Irinotecan and Temozolomide
Phase I- Dose level 1	Irinotecan	Silmitasertib 600 mg/m2 twice a day plus Neuroblastoma: Regimen A: Irinotecan and Temozolomide Sarcoma: Regimen B: Vincristine, Irinotecan and Temozolomide
Phase I- Dose level 1	Temozolomide	Silmitasertib 600 mg/m2 twice a day plus Neuroblastoma: Regimen A: Irinotecan and Temozolomide Sarcoma: Regimen B: Vincristine, Irinotecan and Temozolomide
Phase I- Dose level 2	Temozolomide	Silmitasertib 800 mg/m2 twice a day plus Neuroblastoma: Regimen A: Irinotecan and Temozolomide Sarcoma: Regimen B: Vincristine, Irinotecan and Temozolomide
Phase I- Dose level 2	Vincristine	Silmitasertib 800 mg/m2 twice a day plus Neuroblastoma: Regimen A: Irinotecan and Temozolomide Sarcoma: Regimen B: Vincristine, Irinotecan and Temozolomide
Phase II- Relapsed/refractory Neuroblastoma	Silmitasertib	Silmitasertib RP2D twice a day plus Irinotecan and Temozolomide
Phase II- Relapsed/refractory Ewing sarcoma	Silmitasertib	Silmitasertib RP2D twice a day plus Vincristine, irinotecan and temozolomide
Phase II- Relapsed/refractory Neuroblastoma	Temozolomide	Silmitasertib RP2D twice a day plus Irinotecan and Temozolomide
Phase II- Relapsed/refractory Ewing sarcoma	Temozolomide	Silmitasertib RP2D twice a day plus Vincristine, irinotecan and temozolomide
Phase II- Relapsed/refractory Ewing sarcoma	Irinotecan	Silmitasertib RP2D twice a day plus Vincristine, irinotecan and temozolomide
Phase II- Relapsed/refractory Ewing sarcoma	Vincristine	Silmitasertib RP2D twice a day plus Vincristine, irinotecan and temozolomide

Primary Outcome Measures

Name	Time	Method
Phase I- Number of Participants with Adverse Events as a Measure of Safety and Tolerability	2 years plus 30 days	To characterize the safety profile of silmitasertib in combination with chemotherapy
Phase I- Number of Participants with Dose Limiting Toxicities to determine RP2D	21 days	To determine the Recommended Phase 2 Dose (RP2D) of silmitasertib in combination with chemotherapy
Phase II- Determine the Overall Response Rate (ORR) of Participants using INSS Response	2 years	To evaluate the efficacy of silmitasertib in combination with chemotherapy in 2 disease cohorts, based upon Overall response rate (ORR)

Secondary Outcome Measures

Name	Time	Method
Phase II- Number of Participants with Adverse Events as a Measure of Safety and Tolerability	2 years plus 30 days	To characterize the safety profile of silmitasertib in combination with chemotherapy
Phase I- Determine the Overall Response Rate (ORR) of Participants using INSS Response	2 years	To evaluate the efficacy of silmitasertib in combination with chemotherapy in 2 disease cohorts based upon Overall response rate (ORR)
Number of participants with progression free survival (PFS) during study	2 years	To evaluate the efficacy of silmitasertib in combination with chemotherapy in 2 disease cohorts based upon Progression Free Survival (PFS)
Phase II- Length of time that participants experience Overall Survival (OS)	2 years	To evaluate the efficacy of silmitasertib in combination with chemotherapy in 2 disease cohorts based upon Overall Survival (OS)

Trial Locations

Locations (1)

Penn State Milton S. Hershey Medical Center and Children's Hospital; 🇺🇸 Hershey, Pennsylvania, United States