Breast Cancer
Conditions
Brief summary
The standard or usual treatment for this disease is to undergo chemotherapy to slow the spread of disease and relieve some symptoms of cancer. One of the standard types of chemotherapy is a drug called paclitaxel (Taxol) given in a low dose every week for three out of four weeks. CFI-402257 is a new type of drug for breast cancer. Laboratory tests show that it may help slow the growth of breast cancer. This drug has been shown to shrink tumours in animals. CFI-402257 has been studied in a few people and appears well tolerated with little side effects. CFI-402257 seems promising but it is not clear if it can offer better results when given with paclitaxel compared to paclitaxel alone.
Detailed description
Phase I: The purpose of the first phase of the study is to find the highest dose of CFI-402257 that can be tolerated without causing very severe side effects when receiving paclitaxel. This is done by starting at a dose lower than the one that is tolerated in patients when given on its own. Participants are given CFI-402257 together with paclitaxel and are watched very closely to see what side effects they have and to make sure the side effects are not severe. If the side effects are not severe, then new participants will be given a higher dose of CFI-402257. Participants joining this study later on will get higher doses of CFI-402257 than participants who join earlier. This will continue until a dose is found that causes severe but temporary side effects. Doses higher than that will not be given. Phase II: The purpose of the second phase will be to find out the effect that CFI-402257 has on breast cancer, using doses found to be safe in the first phase of the study, when given with paclitaxel.
Interventions
DRUGCFI-402257
Orally taken on intermittent schedule (days 1, 2, 8, 9, 15 \& 16
DRUGPaclitaxel
80 mg/m2 IV days 1, 8 \& 15 every 28 days
Sponsors
Canadian Cancer Trials Group
Stand Up To Cancer
Canadian Breast Cancer Foundation
Ontario Institute for Cancer Research
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients must have histologically and/or cytologically confirmed diagnosis of breast cancer that is advanced/metastatic/recurrent or unresectable, for which no curative therapy exists, and for which systemic therapy is indicated. Only female patients will be enrolled * All patients must have a formalin fixed paraffin embedded tissue block (from primary or metastatic tumour) available and must have provided informed consent for the release of the block. Biopsies are optional but strongly encouraged for patients with accessible disease suitable for biopsy. The timing of tumour biopsies for patients who provide informed consent and are willing is prior to treatment (after enrollment) and again no later than the end of the day following the day 8 paclitaxel infusion. Lesions planned for biopsy may not be the only target lesion. * Presence of clinically and/or radiologically documented disease. All radiology studies must be performed within 21 days prior to enrollment (within 28 days if negative). For phase Ib, patients are not required to have measurable disease as defined by RECIST 1.1 but must not have bone-only or marker only disease. For phase II, all patients must have measurable disease as defined by RECIST 1.1. The criteria for defining measurable disease are as follows: Chest xray ≥ 20mm; CT scan ≥ 10mm (longest diameter); Physical exam ≥10mm; Lymph nodes by CT scan ≥ 15mm (measured in short axis) * Patients must be ≥18 years of age. * Patients must have an ECOG performance status of 0 or 1. * Patients must be able to swallow oral medications * Patients must have received at least one non-taxane containing chemotherapy regimen for advanced or metastatic disease unless: 1. they have relapsed within 6 months of completion of adjuvant/neoadjuvant chemotherapy and the regiment did not contain taxane, or, 2. they have received taxane and/or anthracycline-containing adjuvant/neoadjuvant chemotherapy 6 or more months prior to relapse or; 3. they have a documented contraindication to palliative chemotherapy other than weekly paclitaxel. * Patients must not be considered appropriate for endocrine therapy and must not have received taxanes in the metastatic setting. * Patients may have received other therapies including endocrine therapy, immunotherapy, and/or targeted therapies (including CDK4/6 inhibitors). * Patient may NOT have had previous exposure to any therapy within the pharmacological class (TTK/MPS1 inhibitor). * Patients must have recovered (to at least grade 0 or 1) from all reversible toxicity other than alopecia related to prior chemotherapy or systemic therapy and have adequate washout as follows: * Longest of one of the following: * Two weeks, * 5 half-lives for investigational agents, * Standard cycle length of standard therapies (e.g. at least 3 weeks for capecitabine. * Prior external beam radiation is permitted provided a minimum of 28 days (4 weeks) have elapsed between the last dose of radiation and date of enrollment. Exceptions may be made for low-dose, non-myelosuppressive radiotherapy after consultation with CCTG. * Previous surgery is permitted provided that a minimum of 21 days (3 weeks) have elapsed between any major surgery and date of enrollment, and wound healing has occurred. * Absolute neutrophils ≥ 1.5 x 10\^9/L * Platelets ≥100 x 10\^9/L * Bilirubin ≤ 1.0 x ULN * AST and ALT ≤3.0 x ULN and ≤ 5.0 x ULN (if patient has liver mets) * Serum creatinine ≤ 1.5 x ULN or * Creatinine clearance ≥ 60mL/min * Women of childbearing potential must have agreed to use a highly effective contraceptive method * Patient consent must be appropriately obtained in accordance with applicable local and regulatory requirements. Each patient must sign a consent form prior to enrollment in the trial to document their willingness to participate. * In accordance with CCTG policy, protocol treatment is to begin within 2 working days of patient enrollment.
Exclusion criteria
* Patients with a history of other untreated malignancies or malignancies which required therapy within the past 2 years. Patients with other malignancies of a nature that do not require treatment may be eligible after consultation with the CCTG. * Patients with HER2 positive breast cancer. * Patients with active or uncontrolled infections or with serious illnesses or medical conditions which would not permit the patient to be managed according to the protocol. * Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction within the previous year or cardiac ventricular arrhythmias requiring medication, history of 2nd or 3rd degree atrioventricular conduction defects). Patients with a significant cardiac history, even if controlled, should ahve a LVEF ≥ 50% * Patients are not eligible if they have a known hypersensitivity to the study drug(s) or their components. * Patients with history of central nervous system metastases or spinal cord compression unless have received definitive treatment, are clinically stable and do not require corticosteroids. * Patients who have contraindications to treatment with paclitaxel and/or neuropathy \> grade 1. * Concurrent treatment with other investigational drugs or anti-cancer therapy. * Pregnant or breastfeeding women. * Prohibited medications as listed in Appendix V Table 1 * Patients treated with full-dose warfarin. Patients with history of deep vein thrombosis or pulmonary embolus who are being treated with therapeutic doses of low molecular weight heparin, direct factor Xa inhibitors or prophylactic dose anticoagulants may be enrolled. * Patients with a medical condition that could impair the administration of oral agents including significant bowel resection, inflammatory bowel disease or uncontrolled nausea or vomiting.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase I: Recommended Phase II Dose for CFI-402257 | During cycle 1 (28 days) | The maximum tolerated dose of CFI-402257 for phase II study identified by a standard 3+3 design to escalate the dose of CFI-402257. |
| Phase II: Overall Response Rate Using RECIST 1.1 | 2 years | Percentage of patients with a complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Phase II: Clinical Benefit Rate Determined by Complete Response, Partial Response or Stable Disease | 2 years | Percentage of patients with a complete response (CR) or partial response (PR), or with stable disease (SD) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), \<30% decrease in the sum of the longest diameter of target lesions but \<20% increase in the sum of the longest diameter of target lesions\>16 weeks of duration; Overall clinical benefit = CR + PR+SD. |
Countries
Canada
Contacts
STUDY_CHAIRPhilippe Bedard
Princess Margaret Cancer Centre, Toronto, ON
STUDY_CHAIRMihaela Mates
Cancer Centre of Southeastern Ontario at Kingston General Hospital, Kingston, ON
Participant flow
Recruitment details
There were five dose levels in the phase I component of this study with respectively 4, 3, 6, 7, and 6 patients enrolled. Based on the results from patients on dose levels 4 and 5, dose level 3 was expanded with 11 additional patients enrolled. From the results of a total of 17 patients enrolled in this dose level, dose level 3 was declared as the recommended phase II dose and all 17 patients enrolled in dose level 3 were considered to be Phase II patients for the analyses.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1 Dose Level 1 (CFI-402257 84 mg + Paclitaxel 80 mg/m2) Oral CFI-402257 84 mg on intermittent schedule: days 1, 2, 8, 9, 15 & 16 q4w Plus Paclitaxel 80 mg/m2 IV days 1, 8 & 15 every 28 days | 4 |
| Phase I Dose Level 2 (CFI-402257 112 mg + Paclitaxel 80 mg/m2) Oral CFI-402257 112 mg on intermittent schedule: days 1, 2, 8, 9, 15 & 16 q4w Plus Paclitaxel 80 mg/m2 IV days 1, 8 & 15 every 28 days | 3 |
| Phase I Dose Level 3 and Expansion Cohort (CFI-402257 168 mg + Paclitaxel 80 mg/m2) Oral CFI-402257 168 mg on intermittent schedule: days 1, 2, 8, 9, 15 & 16 q4w Plus Paclitaxel 80 mg/m2 IV days 1, 8 & 15 every 28 days | 17 |
| Phase I Dose Level 4 (CFI-402257 210 mg + Paclitaxel 80 mg/m2)) Oral CFI-402257 210 mg on intermittent schedule: days 1, 2, 8, 9, 15 & 16 q4w Plus Paclitaxel 80 mg/m2 IV days 1, 8 & 15 every 28 days | 7 |
| Phase I Dose Level 5 (CFI-402257 252 mg + Paclitaxel 80 mg/m2) Oral CFI-402257 252 mg on intermittent schedule: days 1, 2, 8, 9, 15 & 16 q4w Plus Paclitaxel 80 mg/m2 IV days 1, 8 & 15 every 28 days | 6 |
| Total | 37 |
Baseline characteristics
| Characteristic | Phase 1 Dose Level 1 (CFI-402257 84 mg + Paclitaxel 80 mg/m2) | Phase I Dose Level 2 (CFI-402257 112 mg + Paclitaxel 80 mg/m2) | Phase I Dose Level 3 and Expansion Cohort (CFI-402257 168 mg + Paclitaxel 80 mg/m2) | Phase I Dose Level 4 (CFI-402257 210 mg + Paclitaxel 80 mg/m2)) | Phase I Dose Level 5 (CFI-402257 252 mg + Paclitaxel 80 mg/m2) | Total |
|---|---|---|---|---|---|---|
| Age, Continuous | 58 years | 48 years | 58 years | 62 years | 65 years | 59 years |
| ECOG (Eastern Cooperative Oncology Group) Performance Status 0 | 3 Participants | 2 Participants | 5 Participants | 5 Participants | 4 Participants | 19 Participants |
| ECOG (Eastern Cooperative Oncology Group) Performance Status 1 | 1 Participants | 1 Participants | 12 Participants | 2 Participants | 2 Participants | 18 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 1 Participants | 4 Participants | 1 Participants | 0 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 2 Participants |
| Race (NIH/OMB) White | 4 Participants | 2 Participants | 12 Participants | 6 Participants | 5 Participants | 29 Participants |
| Region of Enrollment Canada | 4 participants | 3 participants | 17 participants | 7 participants | 6 participants | 37 participants |
| Sex: Female, Male Female | 4 Participants | 3 Participants | 17 Participants | 7 Participants | 6 Participants | 37 Participants |
| Sex: Female, Male Male | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 4 | 3 / 3 | 16 / 17 | 5 / 7 | 4 / 6 |
| other Total, other adverse events | 4 / 4 | 3 / 3 | 17 / 17 | 7 / 7 | 6 / 6 |
| serious Total, serious adverse events | 2 / 4 | 0 / 3 | 3 / 17 | 2 / 7 | 1 / 6 |
Outcome results
Primary
Phase II: Overall Response Rate Using RECIST 1.1
Percentage of patients with a complete response (CR) or partial response (PR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.
Time frame: 2 years
Population: Participants who received Dose Level 3 in Phase I and in the expansion cohort are combined for analysis of this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CFI-402257 + Paclitaxel | Phase II: Overall Response Rate Using RECIST 1.1 | 1 Participants |
Primary
Phase I: Recommended Phase II Dose for CFI-402257
The maximum tolerated dose of CFI-402257 for phase II study identified by a standard 3+3 design to escalate the dose of CFI-402257.
Time frame: During cycle 1 (28 days)
Population: There were five dose levels in the phase I component of this study with respectively 4, 3, 6, 7, and 6 patients enrolled. Based on the results, dose level 3 was declared as the recommended phase II dose.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| CFI-402257 + Paclitaxel | Phase I: Recommended Phase II Dose for CFI-402257 | 168 mg |
Secondary
Phase II: Clinical Benefit Rate Determined by Complete Response, Partial Response or Stable Disease
Percentage of patients with a complete response (CR) or partial response (PR), or with stable disease (SD) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), \>=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), \<30% decrease in the sum of the longest diameter of target lesions but \<20% increase in the sum of the longest diameter of target lesions\>16 weeks of duration; Overall clinical benefit = CR + PR+SD.
Time frame: 2 years
Population: Participants who received Dose Level 3 in Phase I and in the expansion cohort are combined for analysis of this outcome measure.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| CFI-402257 + Paclitaxel | Phase II: Clinical Benefit Rate Determined by Complete Response, Partial Response or Stable Disease | 8 Participants |