CFI-402257, a Potent and Selective TTK Inhibitor, in Solid Tumors and With Fulvestrant in Breast Cancer

Study Overview
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Brief Summary
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The purpose of this study is to test the safety of an investigational drug called CFI-402257 alone in advanced solid tumors and in combination with Fulvestrant in advanced breast cancer patients.

Detailed Description
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This study will be evaluating the safety and tolerability of CFI-402257 in subjects with advanced solid tumors and in advanced breast cancer. The study is designed to build on encouraging data from another study and to obtain further safety, efficacy, pharmacokinetics (PK) and pharmacodynamics (PD) data of CFI-402257.

Official Title
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A Dose-confirming Study of CFI-402257 as a Single Agent in Advanced Solid Tumors and in Combination With Fulvestrant in Patients With ER+/HER2- Advanced Breast Cancer After Disease Progression on Prior CDK4/6 and Endocrine Therapy

Conditions
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Advanced Solid Tumor, Breast Cancer

Intervention / Treatment
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* Drug: CFI-402257
* Drug: Fulvestrant


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Part A Escalation 1. Have histological or cytological proof of advanced cancer that has progressed on at least 1 prior line of systemic therapy Inclusion Criteria: Part A Expansion Breast cancer patients positive for estrogen receptor and/or progesterone receptor and negative for HER2 Must have previously received a CDK4/6 inhibitor No limit on lines of endocrine therapy Must have received no more than 1 line of cytotoxic chemotherapy Have measurable disease as per RECIST 1.1 guidelines. Inclusion Criteria: Part B Breast cancer patients positive for estrogen receptor and/or progesterone receptor and negative for HER2 Must have previously received a CDK4/6 inhibitor Must have previously received no more than 1 line of endocrine therapy Must have received no more than 1 line of cytotoxic chemotherapy Have measurable disease as per RECIST 1.1 guidelines. Exclusion Criteria: All Parts Are pregnant or nursing. Have received chemotherapy, biological therapy, or investigational treatment less than 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to first dose of study drug. Have received radiotherapy less than 2 weeks prior to first dose of study drug. Received growth factors within 14 days prior to initiation of dosing of CFI-402257 or who will require ongoing treatment with growth factors Have active, acute, or clinically significant chronic infections. Have the following cardiovascular conditions Have uncontrolled severe hypertension Have symptomatic congestive heart failure Have active angina pectoris or recent myocardial infarction Have chronic atrial fibrillation or QTc of greater than 470 msec. Have had major surgery within 21 days of starting therapy. Primary central nervous system malignancies or known central nervous system metastasis. Being treated with full dose warfarin. Coagulopathy or any history of coagulopathy within the past 6 months, including history of deep vein thrombosis or pulmonary embolism. Patients must avoid the use of strong CYP3A4 inducers and inhibitors. CYP3A sensitive substrates, PgP, BCRP inhibitors Have had prior treatment with a TTK/MPS1 inhibitor. Part B only: Known bleeding disorder which would prohibit administration of fulvestrant. Part B only: Concomitant active malignancy other than ER+/HER2- advanced breast cancer. Part A only: Concomitant active malignancy other than primary malignancy Part B only: Had prior treatment with fulvestrant or agents with similar MoA

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Dose escalation and expansion for monotherapy and combination arms with fulvestrant
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A: Monotherapy Escalation and Expansion<br>Dose selection and expansion of CFI-402257 | Drug: CFI-402257<br>* Oral once daily in 28 day cycles<br>* Other names: 402257;|
| Experimental: Part B: Combination Escalation and Expansion<br>Dose selection and expansion of CFI-402257 with Fulvestrant | Drug: CFI-402257<br>* Oral once daily in 28 day cycles<br>* Other names: 402257;Drug: Fulvestrant<br>* 500 mg given by IM injection on Day 1 and Day 15 of Cycle 1 and Day 1 of each subsequent cycle<br>* Other names: Faslodex;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To assess the incidence of adverse events of CFI-402257 as a single agent and at the recommended phase 2 dose (RP2D) | The number of subjects who experience an adverse event that was possibly related to study drug as assessed by CTCAE v 5.0. | 48 months | 
| To assess the incidence of adverse events of CFI-402257 in combination with fulvestrant and at the recommended phase 2 dose (RP2D) | The number of subjects who experience an adverse event that was possibly related to study drug as assessed by CTCAE v 5.0. | 48 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Assessment of objective response rates | Objective response rate will be summarized by dose cohort and overall using the percent of patients in each tumor response category. | 48 months | 
| Assessment of objective response rates of the combination | Objective response rate will be summarized overall for advanced breast cancer patients | 48 months | 
| Assessment of the pharmacokinetic profile of CFI-402257 through AUC | Area under the plasma concentration (AUC) versus time curve from time 0 to time of least measurable concentration tabulated by dose group. | 48 months | 
| Assessment of the pharmacokinetic profile of CFI-402257 in combination with fulvestrant through AUC | Area under the plasma concentration (AUC) versus time curve from time 0 to time of least measurable concentration tabulated by dose group. | 48 months | 
| To evaluate the effect of CFI-402257 treatment on changes in variant allele function | Changes in variant allele function will be measured by looking at circulating tumor deoxyribonucleic acid compared to baseline | 48 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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advanced solid tumors, advanced breast cancer, CFI-402257, 2257, fulvestrant, TWT-203, TWT203, UHN, University Health Network, Treadwell, Treadwell Therapeutics, endocrine therapy, TTK, TTK inhibitor