A Study to Investigate Fadraciclib (CYC065), in Subjects With Advanced Solid Tumors and Lymphoma

Study Overview
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Brief Summary
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This is a 2-part, phase 1/2, open-label, multicenter study designed to evaluate the safety, tolerability, PK, pharmacodynamics, PGx, and efficacy of fadraciclib administered orally BID. This study consists of Phase 1 and Phase 2 components in subjects with advanced solid tumors and lymphoma who have progressed despite having standard therapy or for which no standard therapy exists.

Detailed Description
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Phase 1 part of the study will consist of a dose-escalation and a dose-finding component . Phase 2 will enroll subjects with locally advanced, recurrent, or metastatic, histologically confirmed advanced solid tumors or lymphoma, who have failed all standard therapies or for whom standard therapy does not exist, into 8 groups: Group 1: Endometrial or Ovarian cancer Group 2: Biliary tract cancer Group 3: HCC Group 4: Breast cancer, meeting any of the following criteria: HER-2 refractory MBC HR positive, HER-2 negative, MBC post-CDK4/6 inhibitor Triple-negative breast cancer (TNBC) Group 5: B-cell lymphoma Group 6: T-cell lymphoma (CTCL and PTCL) Group 7: mCRC, including KRAS mutated mCRC Group 8: Basket cohort: Tumor types suspected to have a related mechanism of action such as MCL1, MYC or CCNE amplification/overexpression not included in previous groups.

Official Title
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A Phase 1/2, Open-label, Multicenter Study to Investigate the Safety, Pharmacokinetics, and Efficacy of Fadraciclib (CYC065), an Oral CDK 2/9 Inhibitor, in Subjects With Advanced Solid Tumors and Lymphoma

Conditions
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Solid Tumor, Adult, Lymphoma

Intervention / Treatment
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* Drug: Fadraciclib


Participation Criteria
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Eligibility Criteria
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Inclusion criteria Age ≥ 18 years Subjects with histological- or cytological-confirmed, advanced cancer who have progressed on (or not been able to tolerate) standard therapy or for whom no standard anticancer therapy exists For Phase 1, all tumor types may be enrolled For Phase 2, subjects will be enrolled as per the study design section above ECOG performance status of 0 or 1 Women of childbearing potential (WOCBP) must have a negative pregnancy test (urine or serum) within 7 days prior to starting the study drug. Both males and females must agree to use effective birth control during the study (prior to the first dose and for 6 months after the last dose) if conception is possible during this interval. Subjects must be able to swallow and retain orally administered medication and not have any clinically significant GI abnormalities that may alter the absorption, such as malabsorption syndrome or major resection of the stomach or bowels. Able to agree to and sign t he informed consent and to comply with the protocol. Exclusion criteria Subjects with a history of brain metastases or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases. Subjects with treated brain metastases that are asymptomatic and have been clinically stable for at least 4 weeks will be eligible. Subjects who have not received vaccines for SARS-COV-2 within last 3 months and have suspected signs and symptoms of COVID-19 or a recent history (within 14 days) of contact with any COVID-19 positive subject/isolation/quarantine or subjects with confirmed COVID-19. Subjects with a history of another primary malignancy, other than: Carcinomas in situ, e.g., breast, cervix, and prostate Locally excised nonmelanoma skin cancer No evidence of disease from another primary cancer for 2 or more years and has not taken any anti-cancer treatment in 2 years. Any other clinically significant acute or chronic medical or psychiatric condition or any laboratory abnormality that may increase the risk associated with study drug administration or may interfere with the interpretation of study results. Diseases that significantly affect GI absorption of fadraciclib. Subjects who have impaired cardiac function or clinically significant cardiac disease. Presence of active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) or GI perforation within 6 months of enrollment Presence of an active infection requiring intravenous antibiotics Presence of known history of human immunodeficiency virus-1/2 with uncontrolled viral load and on medications that may interfere with metabolism Presence of active hepatitis B virus (HBV) or hepatitis C virus (HCV). Chemotherapy, biologic therapy, targeted therapy, immunotherapy, extended-field radiotherapy, or investigational agents within 5 half-lives or 3 weeks (whichever is shorter) prior to administration of first dose of study drug on Day 1 or have not recovered from the side effects of such therapy. Major surgery/surgical therapy for any cause within 4 weeks of the first dose

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation in Phase 1 part.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I Dose escalation<br>Phase I = Fadraciclib administered orally in escalating doses starting at 50mg bid MWF for 3 weeks of a 4 week cycle. Subsequent cohorts will escalate in dose and schedule until optimized phase 2 dose and schedule is achieved. Phase 2 = Recommended Fadraciclib phase 2 dose and schedule administered orally in 28 day cycles. | Drug: Fadraciclib<br>* Fadraciclib is a highly selective, orally- and intravenously- available, 2nd generation amino-purine inhibitor of CDK2 and CDK9.<br>* Other names: CYC065;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum tolerated dose | The incidence rate of dose-limiting toxicities (first cycle only) at each dose level | 6 months | 
| Overall Response Rate (ORR) | Assessment of response criteria according to RESIST, Lugano or mSWAT | 18 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse events | Type, frequency, and severity of adverse drug reactions | 24 months | 
| AUC | Fadraciclib plasma concentrations | 6 months | 
| Cmax | Fadraciclib plasma concentrations | 6 months | 
| Tmax | Fadraciclib plasma concentrations | 6 months | 
| T1/2 | Fadraciclib plasma concentrations | 6 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumor, lymphoma