Tesetaxel Plus Reduced Dose of Capecitabine in Patients With HER2 Negative, HR Positive, LA/MBC (CONTESSA 2)

• ClinicalTrials.gov Identifier: NCT03858972
• Recruitment Status: Terminated
• First Posted: March 1, 2019
• Last Update Posted: July 30, 2021
• Sponsor: Odonate Therapeutics, Inc.
• Information provided by (Responsible Party): Odonate Therapeutics, Inc.

Tracking Information

• First Submitted Date: February 26, 2019
• First Posted Date: March 1, 2019
• Last Update Posted Date: July 30, 2021
• Actual Study Start Date: February 5, 2019
• Actual Primary Completion Date: June 11, 2021 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: January 19, 2021): ORR as assessed by the IRC [ Time Frame: Approximately 2.0-2.5 years ]

Original Primary Outcome Measures (submitted: February 28, 2019)

ORR [ Time Frame: Approximately 2 - 2.5 years ]

Objective response rate

Current Secondary Outcome Measures (submitted: January 19, 2021)

• DoR as assessed by the IRC [ Time Frame: Approximately 2.0-2.5 years ]
• PFS as assessed by the IRC [ Time Frame: Approximately 2.0-2.5 years ]
• DCR as assessed by the IRC [ Time Frame: Approximately 2.0-2.5 years ]
• OS [ Time Frame: Approximately 3.0-3.5 years ]
• Central nervous system (CNS) ORR as assessed by the CNS IRC in patients with CNS metastases at baseline [ Time Frame: Approximately 2.0-2.5 years ]
• CNS DoR as assessed by the CNS IRC in patients with CNS metastases at baseline [ Time Frame: Approximately 2.0-2.5 years ]
• CNS PFS as assessed by the CNS IRC in patients with CNS metastases at baseline or a history of CNS metastases and in the intent-to-treat (ITT) population [ Time Frame: Approximately 2.0-2.5 years ]
• CNS OS in patients with CNS metastases at baseline or a history of CNS metastases [ Time Frame: Approximately 3.0-3.5 years ]

Original Secondary Outcome Measures (submitted: February 28, 2019)

• DoR [ Time Frame: Approximately 2 - 2.5 years ]
  Duration of response
• PFS [ Time Frame: Approximately 2 - 2.5 years ]
  Progression-free survival
• DCR [ Time Frame: Approximately 2 - 2.5 years ]
  Disease control rate
• OS [ Time Frame: Approximately 3 - 3.5 years ]
  Overall survival
• CNS ORR in patients with CNS metastases at baseline [ Time Frame: Approximately 2 - 2.5 years ]
  Central nervous system (CNS) objective response rate as assessed by the CNS IRC
• CNS DoR in patients with CNS metastases at baseline [ Time Frame: Approximately 2 - 2.5 years ]
  CNS duration of response as assessed by the CNS IRC
• CNS PFS in patients with CNS metastases at baseline or a history of CNS metastases and in the intent-to-treat (ITT) population [ Time Frame: Approximately 2 - 2.5 years ]
  CNS progression-free survival as assessed by the CNS IRC
• CNS OS in patients with CNS metastases at baseline or a history of CNS metastases [ Time Frame: Approximately 3 - 3.5 years ]
  CNS overall survival

Current Other Pre-specified Outcome Measures (submitted: January 19, 2021)

• Adverse events, including deaths and other serious adverse events [ Time Frame: Approximately 3.0-3.5 years ]
• Incidence of clinical laboratory abnormalities (e.g., CBC, serum chemistry and coagulation testing) [ Time Frame: Approximately 3.0-3.5 years ]
• Peak plasma concentration (Cmax) of tesetaxel [ Time Frame: Approximately 2.0-2.5 years ]
• Area under the plasma concentration versus time curve (AUC) of tesetaxel [ Time Frame: Approximately 2.0-2.5 years ]
• The effect of tesetaxel on capecitabine and 5-FU Cmax [ Time Frame: Approximately 2.0-2.5 years ]
• The effect of tesetaxel on capecitabine and 5-FU AUC [ Time Frame: Approximately 2.0-2.5 years ]

Original Other Pre-specified Outcome Measures (submitted: February 28, 2019)

• Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v5.0 [ Time Frame: Approximately 3 - 3.5 years ]
  Adverse Events will be collected at each visit and at unscheduled visits, as clinically indicated
• Incidence of clinical laboratory abnormalities as assessed by CBC, serum chemistry and coagulation testing [ Time Frame: Approximately 3 - 3.5 years ]
  Laboratory data will be collected at each visit and at unscheduled visits, as appropriate
• Peak plasma concentration (Cmax) of tesetaxel [ Time Frame: Approximately 2 - 2.5 years ]
  Maximum plasma concentration (Cmax) of tesetaxel
• Area under the plasma concentration versus time curve (AUC) of tesetaxel [ Time Frame: Approximately 2 - 2.5 years ]
  Area under the curve (AUC) of tesetaxel
• Peak plasma concentration (Cmax) of capecitabine and 5-FU [ Time Frame: Approximately 2 - 2.5 years ]
  Maximum plasma concentration (Cmax) of capecitabine and 5-FU
• Area under the plasma concentration versus time curve (AUC) of capecitabine and 5-FU [ Time Frame: Approximately 2 - 2.5 years ]
  Area under the curve (AUC) of capecitabine and 5-FU

Descriptive Information

• Brief Title: Tesetaxel Plus Reduced Dose of Capecitabine in Patients With HER2 Negative, HR Positive, LA/MBC
• Official Title: Multinational, Multicenter, Phase 2 Study of Tesetaxel Plus a Reduced Dose of Capecitabine in Patients With HER2 Negative, Hormone Receptor Positive, Locally Advanced or Metastatic Breast Cancer Who Have Not Previously Received a Taxane
• Brief Summary: CONTESSA 2 is a multinational, multicenter, Phase 2 study of tesetaxel in patients with HER2 negative, HR positive, locally advanced or metastatic breast cancer (LA/MBC) not previously treated with a taxane. The primary objective of the study is to establish the efficacy of tesetaxel plus a reduced dose of capecitabine based on objective response rate (ORR) as assessed by an Independent Radiologic Review Committee (IRC). 152 patients were enrolled.
• Detailed Description: CONTESSA 2 is a multinational, multicenter, Phase 2 study of tesetaxel, an investigational, orally administered taxane, in patients with HER2 negative, HR Positive, LA/MBC not previously treated with a taxane in the neoadjuvant, adjuvant or metastatic setting. This Study complements CONTESSA, a multinational, multicenter, randomized, Phase 3 study in patients with HER2 negative, HR positive LA/MBC previously treated with a taxane in the neoadjuvant or adjuvant setting. 152 patients were enrolled, including 149 who received treatment. Patients are administered tesetaxel at 27 mg/m2 orally once every 21 days on the first day of each 21-day cycle plus capecitabine at 825 mg/m2 orally twice daily (for a total daily dose of 1,650 mg/m2) for 14 days of each 21-day cycle. Patients in the dense pharmacokinetics (PK) cohort receive a single dose of capecitabine monotherapy prior to starting the combination regimen. Capecitabine is an oral chemotherapy agent that is considered a standard-of-care treatment in LA/MBC. The primary efficacy endpoint is ORR as assessed by the IRC. The secondary efficacy endpoints are duration of response (DoR) as assessed by the IRC, progression-free survival (PFS) as assessed by the IRC, disease control rate (DCR) as assessed by the IRC and overall survival (OS). CONTESSA 2 also investigates the PK of tesetaxel.
• Study Type: Interventional
• Study Phase: Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Tesetaxel
  Tesetaxel plus reduced dose of capecitabine
• Drug: Capecitabine
  Reduced dose of capecitabine

Study Arms

Experimental: Tesetaxel (oral) and capecitabine (oral)

Cohort 1: Tesetaxel (27 mg/m2) once every 21 days on Day 1 of each 21-day cycle; and capecitabine (825 mg/m2) twice daily (total daily dose of 1,650 mg/m2) beginning with the evening dose on Day 1 through the morning dose on Day 15 of each 21-day cycle.

Cohort 2: On Cycle 1, Day -1, either a single morning dose of capecitabine at 825 mg/m2 (Cohort 2A) or 1,250 mg/m2 (Cohort 2B). On Cycle 1, Day 1, a single dose of tesetaxel (27 mg/m2), followed 2 hours later by capecitabine (825 mg/m2), followed by an evening dose of capecitabine (825 mg/m2). Capecitabine (825 mg/m2) twice daily (total daily dose of 1,650 mg/m2) beginning with the morning dose on Day 2 through evening dose on Day 14 of Cycle 1. Starting with Cycle 2, tesetaxel (27 mg/m2) once every 21 days on Day 1 of each 21-day cycle; and capecitabine (825 mg/m2) twice daily (total daily dose of 1,650 mg/m2) beginning with the evening dose on Day 1 through the morning dose on Day 15 of each 21-day cycle.

Interventions:

• Drug: Tesetaxel
• Drug: Capecitabine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: January 19, 2021): 152
• Original Estimated Enrollment (submitted: February 28, 2019): 125
• Actual Study Completion Date: June 11, 2021
• Actual Primary Completion Date: June 11, 2021 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion criteria:

1. Female or male patients at least 18 years of age
2. Histologically or cytologically confirmed breast cancer
3. HER2 negative disease based on local testing: American Society of Clinical Oncology/College of American Pathologists (ASCO/CAP) guidelines should be utilized for assessing HER2 status
4. HR (ER and/or PgR) positive disease based on local testing: ASCO/CAP guidelines should be utilized for assessing HR status

5. Measurable disease per RECIST 1.1, including bone-only disease with measurable lytic component.

   Patients with bone-only metastatic cancer must have a measurable lytic or mixed lytic-blastic lesion that can be accurately assessed by computed tomography (CT) or magnetic resonance imaging (MRI). Patients with bone-only disease without a measurable lytic component (ie, blastic-only metastasis) are not eligible.

   Known metastases to the CNS are permitted but not required. The following criteria apply:

   • Patients must be neurologically stable and either off corticosteroids or currently treated with a maximum daily dose of 4 mg of dexamethasone (or equivalent), with no increase in corticosteroid dose within 7 days prior to Enrollment (defined as the time of Sponsor approval of treatment dose)
   • Patients with a history of CNS metastases but with no current evidence of CNS lesions following local therapy are eligible
   • Patients may have CNS metastases that are stable or progressing radiologically
   • Patients with current evidence of leptomeningeal disease are not eligible
   • Patients may have untreated brain metastases or previously treated brain metastases, as long as no immediate local CNS-directed therapy is indicated
   • Any prior whole brain radiation therapy must have been completed > 14 days prior to the date of Enrollment
   • Prior stereotactic brain radiosurgery is permitted
   • CNS surgical resection must have been completed > 28 days prior to the date of Enrollment; patient must have complete recovery from surgery
6. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
7. Prior endocrine therapy with or without a CDK 4/6 inhibitor unless endocrine therapy is not indicated (ie, short relapse-free interval while on adjuvant endocrine therapy [endocrine resistance]; rapidly progressing disease/visceral crisis; or endocrine intolerance). Any targeted therapies approved for HER2 negative, HR positive LA/MBC, including everolimus, are permitted as prior therapy. There is no limit to the number of prior endocrine therapies.
8. Documented (including de novo): (a) locally advanced breast cancer that is not considered curable by surgery and/or radiation; or (b) metastatic breast cancer

9. Adequate hematologic, hepatic and renal function, as evidenced by:

   • Absolute neutrophil count (ANC) ≥ 1,500/μL without colony-stimulating factor support
   • Platelet count ≥ 100,000/μL
   • Hemoglobin ≥ 10 g/dL without need for hematopoietic growth factor or transfusion support
   • Total bilirubin < 1.5 × upper limit of normal (ULN); does not apply to patients with Gilbert's syndrome
   • Alanine aminotransferase (ALT) < 3 × ULN unless hepatic metastases are present then < 5 × ULN
   • Aspartate aminotransferase (AST) < 3 × ULN unless hepatic metastases are present then < 5 × ULN
   • Alkaline phosphatase < 2.5 × ULN unless hepatic metastases are present then < 5 × ULN
   • Calculated creatinine clearance ≥ 50 mL/min (by Cockcroft-Gault formula or local standard)
   • Serum albumin ≥ 3.0 g/dL
   • Prothrombin time (PT) < 1.5 × ULN or international normalized ratio (INR) < 1.3 and partial thromboplastin time (PTT) < 1.5 × ULN, unless the patient is on a therapeutic anticoagulant
10. Complete recovery to baseline or Grade 1 per National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 from adverse effects of prior surgery, radiotherapy, endocrine therapy, and other therapy, as applicable, with the exception of Grade 2 alopecia from prior chemotherapy
11. Ability to swallow an oral solid-dosage form of medication
12. A negative serum pregnancy test within 7 days prior to the first dose of Study treatment in women of childbearing potential (ie, all women except those who are post menopause for ≥ 1 year or who have a history of hysterectomy or surgical sterilization)

13. Women of childbearing potential must use an effective, non-hormonal form of contraception from Screening throughout the Treatment Phase and until 70 days after the last dose of Study treatment

    • Acceptable methods include: copper intrauterine device or double barrier methods, including male/female condoms with spermicide and use of contraceptive sponge, cervical cap, or diaphragm

14. Male patients must use an effective, non-hormonal form of contraception from Screening throughout the Treatment Phase and until 130 days after the last dose of Study treatment

    • Acceptable methods include: male/female condoms with spermicide, or vasectomy with medical confirmation of surgical success
15. Written informed consent and authorization to use and disclose health information
16. Ability to comprehend and comply with the requirements of the Study

Exclusion criteria:

1. Two or more prior chemotherapy regimens for advanced disease
2. Prior treatment with a taxane at any dose
3. Prior treatment with capecitabine at any dose
4. Current evidence of leptomeningeal disease
5. Other cancer that required therapy within the preceding 5 years other than adequately treated: (a) non-melanoma skin cancer or in situ cancer; or (b) following approval by the Medical Monitor, other cancer that has a very low risk of interfering with the safety or efficacy endpoints of the Study
6. Known human immunodeficiency virus infection, unless well controlled. Patients who are on an adequate antiviral regimen with no evidence of active infection are considered well controlled.
7. Active hepatitis B or active hepatitis C infection
8. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with Study participation or investigational product administration or may interfere with the interpretation of Study results and, in the judgment of the Investigator, would make the patient inappropriate for entry into this Study.
9. Presence of neuropathy > Grade 1 per NCI CTCAE version 5.0
10. Anticancer treatment, including endocrine therapy, radiotherapy (except stereotactic brain radiosurgery), chemotherapy, biologic therapy, or therapy in an investigational clinical study, ≤ 14 days prior to the date of Enrollment
11. Major surgery ≤ 28 days prior to the date of Enrollment; patient must have complete recovery from surgery
12. Less than 2 weeks or 5 plasma half-lives (whichever is greater) since last use of a medication or ingestion of an agent, beverage, or food that is a known clinically relevant strong inhibitor or known clinically relevant inducer of the cytochrome P450 (CYP)3A pathway (patients should discontinue taking any regularly-taken medication that is a strong inhibitor or inducer of the CYP3A pathway)
13. History of hypersensitivity or unexpected reactions to capecitabine, fluoropyrimidine agents or any of their ingredients
14. Known dihydropyrimidine dehydrogenase (DPD) deficiency. Testing for DPD deficiency must be performed where required by local regulations, using a validated method that is approved by local health authorities.
15. Pregnant or breastfeeding
16. If, in the opinion of the Investigator, the patient is deemed unwilling or unable to comply with the requirements of the Study
17. Treatment with brivudine, sorivudine, or its chemically-related analogs ≤ 28 days prior to the date of Enrollment

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Australia, Canada, Korea, Republic of, Spain, Taiwan, United States

Administrative Information

• NCT Number: NCT03858972
• Other Study ID Numbers: ODO-TE-B201
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

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

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Odonate Therapeutics, Inc.
• Original Responsible Party: Same as current
• Current Study Sponsor: Odonate Therapeutics, Inc.
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Joseph O'Connell, MD; Odonate Therapeutics, Inc.

• PRS Account: Odonate Therapeutics, Inc.
• Verification Date: July 2021