9-ING-41 Plus Carboplatin in Salivary Gland Carcinoma

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 U.S. Food and Drug Administration (FDA) has not approved 9-ING-41 as a treatment for any disease. Carboplatin is used as a treatment for salivary gland cancers, and is approved by the FDA for many cancer types.

9-ING-41 has been identified in other studies as a therapy to block the over-expression of the glycogen synthase kinase-3 beta (GSK-3β) protein, which is thought to be important in signaling cancer growth and to have immune properties. It is believed that GSK-3β is over-expressed in salivary gland cancers and by blocking the action of GSK-3β protein with 9-ING-41 it could slow salivary cancer cell growth that have developed resistance to prior chemotherapy exposure.

The research study procedures include screening for eligibility and study treatment including evaluations and follow-up visits roughly every 3-weeks while on therapy, for up to one year as long as disease does not get worse and the drug therapy remains safe and tolerable.

It is expected that about 33 people treated will take part in this research study.

Actuate Therapeutics is supporting this research study by providing the study drug (9-ING-41) and funding some of the logistics of the trial that are beyond what would be considered standard of care.

• 9-ING-41 (Drug): Intravenous infusion
• Carboplatin (Drug), also known as Paraplatin: Intravenous infusion
• Pembrolizumab (Drug): Intravenous infusion

Primary outcomes

• Objective Response Rate (ORR) [Tumor assessments were performed every 3 cycles (each cycle was 21 days), for up to 15.6 months.]: ORR was defined as the percentage of participants achieving complete response (CR) or partial response (PR) on treatment based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

Secondary outcomes

• Median Progression Free Survival (PFS) [Tumor assessments were performed every 9 weeks for up to 20.2 months.]: PFS based on Kaplan-Meier is defined as the time from registration to the earlier of progressive disease (PD) or death due to any cause. Participants alive without disease progression are censored at date of last disease evaluation. Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.
• Median Overall Survival (OS) [Up to 38.1 months]: Overall survival based on the Kaplan-Meier method is defined as the time from randomization to death. Participants alive are censored at the last date of contact (including lost-to-follow-up) or at the date of withdrawal of consent, if relevant.
• Duration of Response (DOR) [Tumor assessments were performed every 3 cycles (each cycle was 21 days), for up to 15.6 months.]: DOR is defined as the time from date of first documented confirmed objective response to date of first documented progressive disease (PD). Per RECIST 1.1 for target lesions: PD is at least a 20% increase in sum LD, taking as reference the smallest sum on study with at least 5 mm absolute increase. For non-target lesions, progression-free means no new lesions or unequivocal progression on existing non-target lesions or not evaluated.
• Number of Participants With Treatment Related Adverse Events (AE) [AEs were assessed at Day 1 and Day 4 of each 21-day treatment cycle; assessed for up to 16.6 months.]: Number of participants with treatment-related AE is defined as the number of participants who experienced at least one AE assessed as possibly, probably, or definitely related to study treatment according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0.
• Mean Score of Global Question 1 in University of Washington Quality of Life Questionnaire (UW-QOL) [Baseline and off-treatment (end-of-treatment) assessment; maximum treatment duration was 15.6 months.]: UW-QOL Global Question 1 assessed how participants felt relative to before they developed their cancer. The mean score was calculated among all participants who provided a response to this question. Responses were recorded on a 5-point ordinal scale and transformed to a 0-100 score, where 0 = Much worse, 25 = Somewhat worse, 50 = About the same, 75 = Somewhat better, and 100 = Much better.
• Mean Score of Global Question 2 in UW-QOL [Baseline and off-treatment (end-of-treatment) assessment; maximum treatment duration was 15.6 months.]: UW-QOL Global Question 2 assessed patients' health-related QOL during the past 7 days. The mean score was calculated among all participants who provided a response to this question. Responses were recorded on a 6-point ordinal scale and transformed to a 0-100 score, where 0 = Very Poor, 20 = Poor, 40 = Fair, 60 = Good, 80 = Very Good, and 100 = Outstanding.
• Mean Score of Global Question 3 in UW-QOL [Baseline and off-treatment (end-of-treatment) assessment; maximum treatment duration was 15.6 months.]: UW-QOL Global Question 3 assessed patients' overall QOL during the past 7 days. The mean score was calculated among all participants who provided a response to this question. Responses were recorded on a 6-point ordinal scale and transformed to a 0-100 score, where 0 = Very Poor, 20 = Poor, 40 = Fair, 60 = Good, 80 = Very Good, and 100 = Outstanding.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

* Participants must have histologically confirmed salivary gland carcinoma (any histologic subtype, including ACC) with evidence of recurrent, metastatic or advanced, unresectable disease.
* Willing to provide tumor tissue from a diagnostic biopsy or prior surgery.
* Age 18 years or older
* ECOG performance status 0-2 (see Appendix A)
* 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
* 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. This assessment is performed by the treating investigator. Evidence of progression by RECIST v1.1 criteria not required.
* Participants must have at least one RECIST v1.1 measurable non-CNS based lesion, as defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) ≥ 1 cm with CT scans or MR imaging.
* 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); but prior therapy for recurrent/metastatic SGC is not required for participation.
* Ability to understand and the willingness to sign a written informed consent document.

Female subjects of childbearing potential should have a negative urine or serum pregnancy test within 14 days of study registration. Female subjects of childbearing potential should have a negative urine or serum pregnancy test repeated within 72 hours prior to receiving the first dose of study medication. WOCBP will be instructed to adhere to contraception for a period of 90 days after the last dose of investigational product. "Women of childbearing potential (WOCBP)" is defined as any female who has experienced menarche and who has not undergone surgical sterilization (hysterectomy or bilateral oophorectomy) or who is not postmenopausal. Menopause is defined clinically as 12 months of amenorrhea in a woman over 45 in the absence of other biological or physiological causes. In addition, women under the age of 55 must have a documented serum follicle stimulating hormone (FSH) level greater than 40 mIU/mL.

* 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. Women who are not of childbearing potential (i.e., who are postmenopausal or surgically sterile as well as azoospermic men) do not require contraception. See Appendix B for further guidance on contraception.

Exclusion Criteria:

* 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.
* 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.
* Concurrent administration of other cancer specific therapy or investigational agents during the course of this study is not allowed.
* Patients on anticoagulants that require INR monitoring (such as warfarin).
* Uncontrolled intercurrent illness including but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, or cardiac arrhythmia.
* Pregnant or lactating women.
* 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 ears is permitted.

Participant flow

Outcome results

• Objective Response Rate (ORR) (Primary), Number, percentage of participants: Evaluable Patients Popupulation 9.4 (2.0 to 25.0)
• Median Progression Free Survival (PFS) (Secondary), Median, Months: 9-ING-41 + Carboplatin (Part I) 4.3 (2.1 to 12.5); Pembrolizumab + 9-ING-41 + Carboplatin (Part II) 7.3 (1.9 to 11.4)
• Median Overall Survival (OS) (Secondary), Median, Months: 9-ING-41 + Carboplatin (Part I) 15.6 (5.4 to 27.8); Pembrolizumab + 9-ING-41 + Carboplatin (Part II) NA (9.7 to NA)
• Duration of Response (DOR) (Secondary), Median, months: Pembrolizumab + 9-ING-41 + Carboplatin (Part II) 6.9 (2.2 to 7.3)
• Number of Participants With Treatment Related Adverse Events (AE) (Secondary), Number, participants: 9-ING-41 + Carboplatin (Part I) 16; Pembrolizumab + 9-ING-41 + Carboplatin (Part II) 15
• Mean Score of Global Question 1 in University of Washington Quality of Life Questionnaire (UW-QOL) (Secondary), Mean, score on a scale: 9-ING-41 + Carboplatin (Part I) 51.7 +/- 38.3; Pembrolizumab + 9-ING-41 + Carboplatin (Part II) 48.1 +/- 40.1
• Mean Score of Global Question 2 in UW-QOL (Secondary), Mean, score on a scale: 9-ING-41 + Carboplatin (Part I) 48.8 +/- 24.2; Pembrolizumab + 9-ING-41 + Carboplatin (Part II) 58.5 +/- 23.8
• Mean Score of Global Question 3 in UW-QOL (Secondary), Mean, score on a scale: 9-ING-41 + Carboplatin (Part I) 55 +/- 29.7; Pembrolizumab + 9-ING-41 + Carboplatin (Part II) 61.3 +/- 19.7

Adverse events

Time frame: Adverse events were followed up to 16.6 months. Survival status was followed up to 38.1 months.

Serious adverse events by term

Other adverse events by term

86 more terms not shown.

Limitations and caveats: Smaller overall sample size limiting some subgroup analyses.

• Study Protocol and Statistical Analysis Plan (PDF, 2024-02-25)

• Glenn J Hanna, MD, Principal investigator, Dana-Farber Cancer Institute