9-ING-41 Plus Carboplatin in Patients With Advanced, Metastatic Salivary Gland Carcinoma

• ClinicalTrials.gov Identifier: NCT04832438
• Recruitment Status: Withdrawn
• First Posted: April 5, 2021
• Last Update Posted: February 22, 2022
• Sponsor: Actuate Therapeutics Inc.
• Information provided by (Responsible Party): Actuate Therapeutics Inc.

Study Description

Brief Summary:

9-ING-41 is a small molecule potent selective GSK-3β inhibitor with antitumor activity. This study investigates 9-ING-41 in combination with carboplatin chemotherapy in patients with incurable, recurrent or metastatic salivary gland carcinomas (SGC). Patients with advanced SGC (including all histologic subtypes and adenoid cystic carcinoma [ACC]) will receive 9-ING-41 intravenously (IV) along with carboplatin IV at standard dosing together on Day 1, and 9-ING-41 alone on Day 4 of a 21-day cycle. Participants will be enrolled to two histologic cohorts: Cohort 1 will be comprised of those with ACC, and Cohort 2 will include patients with non-ACC SGC (or all other salivary gland cancer histologies). Treatment will continue until progression of disease, death, or discontinuation of therapy for any reason.

Condition or disease	Intervention/treatment	Phase
Salivary Gland Carcinoma; Adenoid Cystic Carcinoma; Salivary Gland Cancer; Salivary Gland Neoplasms	Drug: 9-ING-41; Drug: Carboplatin	Phase 2

Detailed Description:

9-ING-41 is a small molecule potent selective GSK-3β inhibitor with antitumor activity. It acts through downregulation of NF-κB and decreases the expression NF-κB target genes cyclin D1, Bcl-2, anti-apoptotic protein (XIAP) and B-cell lymphoma-extra large (Bcl-XL) leading to inhibition of tumor growth in multiple solid tumor cell and lymphoma lines and patient derived xenograft (PDX) models. 9-ING-41 may also function as an immune modulatory agent by decreasing checkpoint expression and enhancement of T-cell / NK-cell effector function. This is a phase 2, open-label, non-randomized, single institution study investigating the novel glycogen synthase kinase-3 beta (GSK-3β) inhibitor 9-ING-41 in combination with carboplatin chemotherapy in patients with incurable, recurrent or metastatic salivary gland carcinomas (SGC). The safety of this combination has been established in the Actuate 1801 study. Thirty-one evaluable patients with advanced SGC (including all histologic subtypes and adenoid cystic carcinoma [ACC]) will receive 9-ING-41 intravenously (IV) along with carboplatin IV at standard dosing together on Day 1, and 9-ING-41 alone on Day 4 of a 21-day cycle. Participants will be enrolled to two histologic cohorts: Cohort 1 will be comprised of those with ACC, and Cohort 2 will include patients with non-ACC SGC (or all other salivary gland cancer histologies). Treatment will continue until progression of disease, death, or discontinuation of therapy for any reason.

The primary aim of the study is to assess the overall response rate (ORR) as defined by RECIST v1.1 in the overall study population (including both Cohorts 1 and 2). Secondary aims include assessing progression-free survival (PFS), overall survival (OS), determining safety and tolerability, measuring patient-reported quality of life metrics, and correlating efficacy with molecular and immunologic predictors of response. We hypothesize that the novel combination of a GSK-3β inhibitor with carboplatin chemotherapy will result in an ORR of 25% or greater in this patient population where no approved therapies have been established.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 0 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 2 Study of 9-ING-41, a Glycogen Synthase Kinase 3 Beta (GSK 3β) Inhibitor, Plus Carboplatin in Patients With Advanced, Metastatic Salivary Gland Carcinoma
• Estimated Study Start Date: December 18, 2030
• Estimated Primary Completion Date: June 18, 2033
• Estimated Study Completion Date: June 18, 2034

Arms and Interventions

Arm	Intervention/treatment
Experimental: 9-ING-41 plus carboplatin; Patients will receive 9-ING-41 (15 mg/kg IV on Day 1 and Day 4) in addition to carboplatin (AUC 5 IV on Day 1) each of a 21-day cycle	Drug: 9-ING-41; 15 mg/kg as intravenous infusion on Days 1 and Day 4 of a 21-day cycle; Drug: Carboplatin; Carboplatin AUC 5 intravenously on Day 1 of a 21-day cycle

Outcome Measures

Primary Outcome Measures :

1. Number of evaluable patients with objective response as measured by RECIST version 1.1 [ Time Frame: 3-24 months ]
   Response and progression will be evaluated in this study using the international Response Evaluation Criteria in Solid Tumors (RECIST) guideline (version 1.1). Changes in the largest diameter (unidimensional measurement) of the tumor lesions and the shortest diameter in the case of malignant lymph nodes are used in the RECIST criteria.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Participants must have histologically confirmed salivary gland carcinoma (any histologic subtype, including ACC) with evidence of recurrent, metastatic or advanced, unresectable disease.
2. Willing to provide tumor tissue from a diagnostic biopsy or prior surgery.
3. Age 18 years or older
4. ECOG performance status 0-2 (see Appendix A)

5. Participant must have organ and marrow function as defined below within 14 days prior to study registration:

   • leukocytes ≥ 3,000/mcL
   • absolute neutrophil count ≥ 500/mcL
   • hemoglobin ≥ 8.5 g/dL
   • platelets ≥ 75,000/mcL
   • total bilirubin ≤ 2.0 g/dL
   • AST(SGOT)/ALT(SGPT) ≤ 2.5× institutional upper limit of normal
   • creatinine within normal institutional limits OR
   • creatinine clearance ≥50 mL/min/1.73 m2 for participants with creatinine levels above institutional normal
6. Participants must have documentation of a new or progressive lesion on a radiologic imaging study performed within 12 months prior to study registration (progression of disease over any interval is allowed) and/or new or worsening disease-related symptoms within 12 months prior to study registration.
7. Participants must have at least one RECIST v1.1 measurable non-CNS based lesion.
8. Prior systemic therapy: At least 2 weeks must have elapsed since the end of prior chemotherapy, biological agents (3 weeks for anti-cancer monoclonal antibody containing regimens) or any investigational drug product, with adequate recovery of treatment-related toxicity to NCI CTCAE Version 5.0 grade ≤1 (or tolerable grade 2) or back to baseline (except for alopecia or neuropathy). Any number of prior therapies for recurrent/metastatic SGC are permitted (including prior carboplatin exposure).
9. Ability to understand and the willingness to sign a written informed consent document.
10. Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 72 hours prior to the start of study treatment.
11. Men who are sexually active with WOCBP must agree to use any contraceptive method with a failure rate of less than 1% per year. Men who are sexually active with WOCBP will be instructed to adhere to contraception for a period of 90 days after the last dose of investigational product.

Exclusion Criteria:

1. Metastatic disease impinging on the spinal cord or threatening spinal cord compression. Patients that have had previous treatment of disease with impinging on the cord with either surgery or radiotherapy with clinical or radiographic evidence of response or stability are eligible.
2. Participant has known active central nervous system (CNS) metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of trial treatment), and have no evidence of new or enlarging brain metastases.
3. Concurrent administration of other cancer specific therapy or investigational agents during the course of this study is not allowed.
4. Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
5. Pregnant or lactating women.
6. Has a known additional malignancy that is progressing or requires active treatment. Exceptions include: basal cell carcinoma of the skin or squamous cell carcinoma of the skin that has undergone potentially curative therapy or in situ cervical cancer, and low-risk prostate adenocarcinoma being managed with active surveillance. A history of another separate malignancy in remission without evidence of active disease in the last 2 years is permitted.

Contacts and Locations

Locations

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

Sponsors and Collaborators

Actuate Therapeutics Inc.

Investigators

• Principal Investigator: Glenn J Hanna, MD; Dana-Farber Cancer Institute

More Information

• Responsible Party: Actuate Therapeutics Inc.
• ClinicalTrials.gov Identifier: NCT04832438
• Other Study ID Numbers: 2102
• First Posted: April 5, 2021
• Last Update Posted: February 22, 2022
• Last Verified: September 2021

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: No

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Actuate Therapeutics Inc.:

advanced; metastatic; 9-ING-41; carboplatin; refractory

Additional relevant MeSH terms:

Carcinoma; Salivary Gland Neoplasms; Carcinoma, Adenoid Cystic; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Mouth Neoplasms; Head and Neck Neoplasms; Neoplasms by Site; Mouth Diseases; Stomatognathic Diseases; Salivary Gland Diseases; Adenocarcinoma; Carboplatin; Antineoplastic Agents