Open-Label Study to Evaluate the Safety, Tolerability, PK, and Efficacy of INX-315 in Patients With Advanced Cancer (INX-315-01)

• ClinicalTrials.gov Identifier: NCT05735080
• Recruitment Status: Recruiting
• First Posted: February 21, 2023
• Last Update Posted: May 23, 2023
• Sponsor: Incyclix Bio
• Information provided by (Responsible Party): Incyclix Bio

Study Description

Brief Summary:

Incyclix Bio (Incyclix) is developing INX-315 as an oral, small molecule inhibitor of cyclin dependent kinase 2 (CDK2) for the treatment of human cancers. This first-in-human study is designed to evaluate the safety, tolerability, pharmacokinetics (PK) and preliminary antitumor activity of INX-315 in patients with recurrent advanced/metastatic cancer, including hormone receptor positive (HR+)/Human Epidermal Growth Factor Receptor 2 Negative (HER2-) breast cancer who progressed on a prior cyclin-dependent kinase 4/6 inhibitor (CDK4/6i) regimen, and CCNE1-amplified solid tumors who progressed on standard of care treatment. This study will evaluate approximately 6 dose levels of daily INX-315 in Part A, at least two dose levels will be evaluated in Part B to identify the Recommended Phase 2 Dose (RP2D) in patients with ovarian cancer, and Part C will evaluate combination treatment of INX-315 plus a CDK4/6i and selective estrogen receptor degrader (SERD) in HR+/HER2- breast cancer patients who have progressed on prior CDK4/6i regimen.

Condition or disease	Intervention/treatment	Phase
Breast Cancer; Breast Cancer Metastatic; Hormone Receptor Positive Tumor; Human Epidermal Growth Factor 2 Negative Carcinoma of Breast; Ovarian Cancer; CCNE1 Amplification; Solid Tumor; Advanced Cancer; Metastatic Cancer	Drug: INX-315	Phase 1; Phase 2

Detailed Description:

Study INX-315-01 is a first-in-human, Phase 1/2, open-label, dose escalation and dose-expansion study to evaluate the safety, PK, and preliminary antitumor activity of INX-315 in patients with advanced/metastatic cancers. The study will be conducted in 3 parts: Part A (dose escalation) and Part B (ovarian cancer dose expansion) and Part C (breast cancer dose escalation lead-in and expansion).

Part A is the dose-escalation portion of the study to evaluate the safety, tolerability, and PK of INX-315 monotherapy. Dosing decisions will be guided using a Bayesian optimal interval (BOIN) design. Up to 51 patients with recurrent advanced/metastatic cancer, including patients with HR+/HER2- breast cancer who progressed on a prior CDK4/6i regimen, and solid tumors, including ovarian cancer with known amplification of CCNE1 are planned to be enrolled in Part A.

Dose-limiting toxicities (DLTs) will be assessed during the first treatment cycle, i.e., the first 28 days of treatment (the DLT period). Patients who are evaluable for DLT assessment are those patients who are enrolled, received ≥80% of the planned study drug doses and all study visits during the DLT assessment period, and complete the 28-day DLT period.

Part B will expand at least two dose levels determined by the SMC. Part B will enroll patients with platinum-refractory or platinum-resistant advanced/metastatic ovarian cancer patients with CCNE1 amplifications. Part B will open for enrollment once the SMC has selected the dose levels to be evaluated from the Part A portion of the study. Part A patients cannot re-join or continue the study in Part B. Approximately 30 patients will be equally randomized to receive one of the dose levels of INX-315.

Part C will be an expansion cohort, patients with ER+/HER2- breast cancer will be enrolled in this cohort.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 81 participants
• Allocation: Non-Randomized
• Intervention Model: Sequential Assignment

Intervention Model Description

Part A will be a dose escalation guided by BOIN design for treatment assignment and dosing rules.

Part B will be dose expansion, patients will be randomly assigned to receive one of the identified doses of INX-315 in monotherapy

Part C will be dose expansion, patients will receive INX-315 in combination treatment with CDK4/6i and endocrine therapy

• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2, Open-Label Study to Evaluate the Safety, Tolerability, Pharmacokinetics, and Efficacy of INX-315 in Patients With Advanced Cancer
• Actual Study Start Date: March 28, 2023
• Estimated Primary Completion Date: December 2025
• Estimated Study Completion Date: June 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Part A: Dose Escalation; Multiple doses of INX-315 monotherapy, oral administration	Drug: INX-315; Oral administration
Experimental: Part B: Ovarian Dose Expansion; INX-315 monotherapy, oral administration	Drug: INX-315; Oral administration
Experimental: Part C: ER+/HER2- BC Dose Expansion; INX-315 in combination with CDK4/6i and endocrine therapy, oral administration	Drug: INX-315; Oral administration

Outcome Measures

Primary Outcome Measures :

1. Part A and B: Evaluate the incidents of treatment emergent adverse events and laboratory abnormalities [ Time Frame: Up to 12 months ]
2. Part A: Evaluate the occurrence of dose-limiting toxicities (DLTs) during Cycle 1 [ Time Frame: 28 days ]
3. Part A: Recommend at least two doses of INX-315 to be evaluated in the expansion phase [ Time Frame: Up to 12 months ]
4. Part B: Overall response rate (ORR) [ Time Frame: Up to 36 months ]
5. Part B: Selection of Recommended Phase 2 Dose (RP2D) [ Time Frame: Up to 36 months ]

Secondary Outcome Measures :

1. Part A and B: Characterize the maximum plasma concentration (Cmax) [ Time Frame: Cycle 1 Day 1 and Day 15 ]
2. Part A and B: Characterize the time to maximum plasma concentration (Tmax) [ Time Frame: Cycle 1 Day 1 and Day 15 ]
3. Part A and B: Characterize the Area under the plasma concentration versus time curve from time 0 to the end of the dosing interval (AUC0-24h) [ Time Frame: Cycle 1 Day 1 and Day 15 ]
4. Part A and B: Characterize the terminal half-life (t1/2) [ Time Frame: Cycle 1 Day 1 and Day 15 ]
5. Part A and B: Characterize the oral clearance (CL/F) [ Time Frame: Cycle 1 Day 1 and Day 15 ]
6. Part A: Overall response rate (ORR) [ Time Frame: Up to 36 months ]
7. Part A and B: Disease control rate (DCR) [ Time Frame: Up to 36 months ]
8. Part A and B: Progression free survival (PFS) [ Time Frame: Up to 36 months ]
9. Part A and B: Duration of response (DOR) [ Time Frame: Up to 36 months ]
10. Part A and B: Time to progression (TTP) [ Time Frame: Up to 36 months ]
11. Part A and B: Overall survival (OS) [ Time Frame: Up to 36 months ]

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. Advanced unresectable or metastatic ER+/HER2- BC that has progressed following treatment with a CDK4/6 inhibitor
2. Advanced/ metastatic platinum-resistant or platinum-refractory epithelial ovarian cancer (including fallopian tube cancer/primary peritoneal cancer) CCNE1 amplified tumors that progressed after standard systemic therapy
3. Advanced or metastatic solid tumor with known amplification of CCNE1that has progressed after standard therapy, been intolerant to or is ineligible for standard therapy
4. At least one measurable lesion as defined by RECIST v1.1 that has not previously been irradiated
5. ECOG performance status score of 0 or 1.

6. Adequate organ function as demonstrated by the following laboratory values:

   1. Hemoglobin ≥ 9.0 g/dL
   2. Absolute neutrophil count (ANC) ≥ 1.5 × 109/L
   3. Platelet count ≥ 100 × 109/L
   4. Estimated glomerular filtration rate (eGFR) of ≥60 mL/min
   5. Total bilirubin ≤ 1.5 × ULN; AST and ALT ≤ 2.5 × ULN; ≤ 5 × ULN in the presence of liver metastases
7. Negative pregnancy test

Exclusion Criteria:

1. Have received previous therapy with a CDK2/4/6 inhibitor, CDK2 inhibitor, PKMYT1 inhibitor, or WEE1 inhibitor.
2. Have central nervous system (CNS) metastases or spinal cord compression that is associated with progressive neurological symptoms or requires corticosteroids (within 4 weeks of enrollment) to control the CNS disease.
3. Have known intracranial hemorrhage and/or bleeding diatheses.
4. Have visceral crisis, lymphangitic spread, or leptomeningeal carcinomatosis.
5. Have clinically active ongoing interstitial lung disease (ILD) of any etiology, including drug-induced ILD, and radiation pneumonitis within 28 days prior to initiation of study treatment.
6. Resting QTcF > 470 msec, a history of prolonged QT syndrome or Torsades de pointes, or a familial history of prolonged QT syndrome.
7. Uncontrolled, cardiovascular disease (including hypertension) with or without medication
8. History of other malignancies, except for the following: (1) adequately treated basal or squamous cell carcinoma of the skin; (2) curatively treated a) in situ carcinoma of the uterine cervix, b) prostate cancer, or c) superficial bladder cancer; or (3) other curatively treated solid tumor with no evidence of disease for ≥ 3 years.
9. Known HIV infection, including AIDS-related illness, or have active, uncontrolled infection (viral, bacterial, or fungal), including tuberculosis, hepatitis B virus, hepatitis C virus, or COVID-19 infection (symptoms and a positive test result).
10. Requires treatment with a prohibited medication or herbal remedy that cannot be discontinued at least 2 weeks before the start of study drug administration.
11. Have planned or anticipation of the need for major surgical procedure within 28 days of the first dose of study drug (procedures such as central venous catheter placement, tumor needle biopsy, and feeding tube placement are not considered major surgical procedures).
12. Unwilling or unable to comply with scheduled visits, study drug administration plan, laboratory tests, or other study procedures and study restrictions.
13. Radical radiotherapy within 28 days prior to study entry or palliative radiotherapy within 2 weeks prior to study entry.
14. Systemic anti-cancer therapy within 28 days or at least 5 half-lives, whichever is less, prior to the first dose of the study drug
15. Prior irradiation to >25% of the bone marrow
16. Previous high-dose chemotherapy requiring prior stem cell transplant
17. Participation in other studies involving investigational drug(s) within 4 weeks prior to study entry.
18. Known or suspected hypersensitivity to active ingredient/excipients in INX-315.
19. Known difficulty in swallowing or tolerating oral medications, or conditions which would impair absorption of oral medications

Contacts and Locations

Contacts

Contact: Clinical Director; 1-919-328-0003; clinicalinfo@incyclixbio.com

Locations

United States, Massachusetts

Dana-Farber Cancer Institute; Not yet recruiting

Boston, Massachusetts, United States, 02215

Principal Investigator: Antonio Giordano, MD

United States, North Carolina

Levine Cancer Institute (LCI)- Atrium Health; Not yet recruiting

Charlotte, North Carolina, United States, 28204

Principal Investigator: Antoinette Tan, MD

Duke Cancer Center/ DUMC; Not yet recruiting

Durham, North Carolina, United States, 27705

Principal Investigator: Carey Anders, MD

United States, Ohio

Gabrail Cancer Research Center; Recruiting

Canton, Ohio, United States, 44718

Contact: Carrie Smith, RN csmith@gabrailcancercenter.com

Principal Investigator: Nashat Gabrail, MD

Australia, Victoria

Peter MacCallum Cancer Center; Recruiting

Parkville, Victoria, Australia, 3052

Contact: Kim Nayeon Nayeon.Kim@petermac.org

Principal Investigator: George Au-Yeung, MD

Sponsors and Collaborators

Incyclix Bio

More Information

• Responsible Party: Incyclix Bio
• ClinicalTrials.gov Identifier: NCT05735080
• Other Study ID Numbers: INX-315-01
• First Posted: February 21, 2023
• Last Update Posted: May 23, 2023
• Last Verified: May 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Supporting Materials: Study Protocol
• Time Frame: Data will be shared at the completion of the study, expected release date will be in 2026.

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

Keywords provided by Incyclix Bio:

CDK2; CDK4/6i; cyclin dependent kinase 2; CCNE1

Additional relevant MeSH terms:

Neoplasms; Breast Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases