Clinical trial NCT05735080: Open-Label Study to Evaluate the Safety, Tolerability, PK, and Efficacy of INX-315 in Patients With Advanced Cancer
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: 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
Keywords: CDK2
CDK4/6i
cyclin dependent kinase 2
CCNE1
Lead sponsor: Incyclix Bio
Sponsor class: INDUSTRY
First posted: 2023-02-21
Enrollment: 150
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
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 abemaciclib and fulvestrant
Primary purpose: TREATMENT

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. The study will be conducted in 3 parts: Part A (INX-315 monotherapy dose escalation and combination therapy with fulvestrant), Part B (ovarian cancer INX-315 monotherapy dose expansion), and Part C (INX-315 combination therapy with abemaciclib \[a CDK4/6i\] and fulvestrant \[a SERD\] in advanced/metastatic breast cancer; dose escalation and expansion).

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 combination therapy) 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 60 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 during the DLT assessment period, and complete the 28-day DLT period.

Additionally, Part A will have two cohorts that will include INX-315 plus fulvestrant in HR+/HER2- patients who have have had prior treatment with CDK4/6i.

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 HR+/HER2- breast cancer will be enrolled in this cohort. Patients will receive INX-315 along with abemaciclib and fulvestrant. Approximately 50 patients will be enrolled in Part C.

Eligibility 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) CCNE-1 amplified tumors that progressed after standard systemic therapy
3. Advanced or metastatic solid tumor with known amplification of CCNE-1 that 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. Part A and B: Total bilirubin ≤ 1.5 × ULN; AST and ALT ≤ 2.5 × ULN; ≤ 5 × ULN in the presence of liver metastases Part C: Patients with GIlbert's syndrome with a total bilirubin ≤ 2.0 × ULN and direct bilirubin within normal limits
7. Negative pregnancy test

Exclusion Criteria:

1. Have received previous therapy with a CDK2/4/6 inhibitor or CDK2 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 or fulvestrant or abemaciclib.
19. Known difficulty in swallowing or tolerating oral medications, or conditions which would impair absorption of oral medications such as active inflammatory gastrointestinal disease, uncontrolled nausea or vomiting (i.e., CTCAE ≥ Grade 3 despite antiemetic therapy), ongoing gastrointestinal obstruction/motility disorder/active inflammation, malabsorption syndrome, chronic diarrhea, known diverticular disease or previous gastric resection or lap band surgery.
20. Has a serious and/or uncontrolled pre-existing medical condition(s) that, in the judgment of the Investigator or the Sponsor, would preclude participation in this study (for example but not limited to, interstitial lung disease, severe dyspnea at rest or requiring oxygen therapy, history of major surgical resection involving the stomach or small bowel, or preexisting Crohn's disease or ulcerative colitis or a preexisting chronic condition resulting in baseline Grade 2 or higher diarrhea)

Primary outcomes:
measure: Part A and B: Evaluate the incidents of treatment emergent adverse events and laboratory abnormalities in INX-315 monotherapy and in combination with fulvestrant
timeFrame: Up to 12 months
measure: Part A: Evaluate the occurrence of dose-limiting toxicities (DLTs) during Cycle 1
timeFrame: 28 days
measure: Part A: Recommend at least two doses of INX-315 to be evaluated in the expansion phase
timeFrame: Up to 12 months
measure: Part B: Overall response rate (ORR)
timeFrame: Up to 36 months
measure: Part B: Selection of Recommended Phase 2 Dose (RP2D)
timeFrame: Up to 36 months
measure: Part C Evaluate the incidents of treatment emergent adverse events and laboratory abnormalities for patients in combination treatment (INX_315+abemaciclib+fulvestrant)
timeFrame: Up to 12 months
measure: Part C - Evaluate the antitumor activity of INX-315 in combination with abemaciclib and fulvestrant
timeFrame: Up to 12 months
Secondary outcomes:
measure: Characterize the maximum plasma concentration (Cmax)
timeFrame: Cycle 1 Day 1 and Day 15
measure: Characterize the time to maximum plasma concentration (Tmax)
timeFrame: Cycle 1 Day 1 and Day 15
measure: Characterize the Area under the plasma concentration versus time curve from time 0 to the end of the dosing interval (AUC0-24h)
timeFrame: Cycle 1 Day 1 and Day 15
measure: Characterize the terminal half-life (t1/2)
timeFrame: Cycle 1 Day 1 and Day 15
measure: Characterize the oral clearance (CL/F)
timeFrame: Cycle 1 Day 1 and Day 15
measure: Part A: Overall response rate (ORR)
timeFrame: Up to 36 months
measure: Disease control rate (DCR)
timeFrame: Up to 36 months
measure: Progression free survival (PFS)
timeFrame: Up to 36 months
measure: Duration of response (DOR)
timeFrame: Up to 36 months
measure: Time to progression (TTP)
timeFrame: Up to 36 months
measure: Overall survival (OS)
timeFrame: Up to 36 months
measure: Part C Determine recommended dose of INX-315 in combination treatment for further study
timeFrame: Up to 12 months
Other outcomes:
Locations:
city: Atlanta
country: United States
facility: Emory Winship Cancer Institute
state: Georgia
city: Augusta
country: United States
facility: Georgia Cancer Center at Augusta University
state: Georgia
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Institute
state: Michigan
city: Charlotte
country: United States
facility: Levine Cancer Institute (LCI)- Atrium Health
state: North Carolina
city: Durham
country: United States
facility: Duke Cancer Center/ DUMC
state: North Carolina
city: Canton
country: United States
facility: Gabrail Cancer Research Center
state: Ohio
city: Dallas
country: United States
facility: UTSW Medical Center
state: Texas
city: Parkville
country: Australia
facility: Peter MacCallum Cancer Center
state: Victoria
city: South Brisbane
country: Australia
facility: Mater Hospital
Study officials:
References: