Tesetaxel Plus Reduced Dose of Capecitabine vs. Capecitabine in HER2 Negative, HR Positive, LA/MBC (CONTESSA)

• ClinicalTrials.gov Identifier: NCT03326674
• Recruitment Status: Terminated
• First Posted: October 31, 2017
• Last Update Posted: July 30, 2021
• Sponsor: Odonate Therapeutics, Inc.
• Information provided by (Responsible Party): Odonate Therapeutics, Inc.

Tracking Information

• First Submitted Date: October 13, 2017
• First Posted Date: October 31, 2017
• Last Update Posted Date: July 30, 2021
• Actual Study Start Date: December 21, 2017
• Actual Primary Completion Date: August 24, 2020 (Final data collection date for primary outcome measure)
• Current Primary Outcome Measures (submitted: January 19, 2021): PFS as assessed by the IRC [ Time Frame: Approximately 2.5-3.0 years ]

Original Primary Outcome Measures (submitted: October 25, 2017)

PFS [ Time Frame: Approximately 2.5 - 3 years ]

Progression Free Survival

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

• OS [ Time Frame: Approximately 5.0-5.5 years ]
• ORR as assessed by the IRC [ Time Frame: Approximately 2.5-3.0 years ]
• DCR as assessed by the IRC [ Time Frame: Approximately 2.5-3.0 years ]
• Central nervous system (CNS) ORR as assessed by the CNS IRC in patients with CNS metastases at baseline [ Time Frame: Approximately 2.5-3.0 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 2.5-3.0 years ]
• CNS OS in patients with CNS metastases at baseline or a history of CNS metastases [ Time Frame: Approximately 2.5-3.0 years ]

Original Secondary Outcome Measures (submitted: October 25, 2017)

• OS [ Time Frame: Approximately 5 - 5.5 years ]
  Overall Survival
• ORR [ Time Frame: Approximately 2.5 - 3 years ]
  Objective Response Rate
• DCR [ Time Frame: Approximately 2.5 - 3 years ]
  Disease Control Rate

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

• European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire-C30 (EORTC QLQ-C30) Global Health Status/QoL [ Time Frame: Approximately 2.5-3.0 years ]
• EORTC QLQ-C30 Functional Scales and Symptom Scales/Items [ Time Frame: Approximately 2.5-3.0 years ]
• Adverse events, including deaths and other serious adverse events [ Time Frame: Approximately 5.0-5.5 years ]
• Incidence of clinical laboratory abnormalities (e.g., CBC, serum chemistry and coagulation testing) [ Time Frame: Approximately 5.0-5.5 years ]
• Peak plasma concentration (Cmax) of tesetaxel [ Time Frame: Approximately 2.5-3.0 years ]
• Area under the plasma concentration versus time curve (AUC) of tesetaxel [ Time Frame: Approximately 2.5-3.0 years ]

Original Other Pre-specified Outcome Measures (submitted: October 25, 2017)

• PRO [ Time Frame: Approximately 2.5 - 3 years ]
  Patient Reported Outcomes - EORTC QLQ-C30 Global Health Status
• Incidence of Treatment-Emergent Adverse Events as assessed by CTCAE v4.03 [ Time Frame: Approximately 5 - 5.5 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 5 - 5.5 years ]
  Laboratory data will be collected at each visit, and unscheduled visits as appropriate
• Peak plasma concentration (Cmax) of tesetaxel [ Time Frame: Up to 30 minutes pre-dose on Day 1 of Cycles 1, 2, 3 and 4 (cycles are 21 days), 0.5, 1, 2, 3, 4, 5 and 6 hours post dose on Day 1 of Cycles 1, 2, 3 and 4 (cycles are 21 days) and on Day 8 and 15 of Cycles 1 and 3 (cycles are 21 days). ]
  Maximum plasma concentration (Cmax) of tesetaxel
• Area under the plasma concentration versus time curve (AUC) of tesetaxel [ Time Frame: Up to 30 minutes pre-dose on Day 1 of Cycles 1, 2, 3 and 4 (cycles are 21 days), 0.5, 1, 2, 3, 4, 5 and 6 hours post dose on Day 1 of Cycles 1, 2, 3 and 4 (cycles are 21 days) and on Day 8 and 15 of Cycles 1 and 3 (cycles are 21 days). ]
  Area under the curve (AUC) of tesetaxel

Descriptive Information

• Brief Title: Tesetaxel Plus Reduced Dose of Capecitabine vs. Capecitabine in HER2 Negative, HR Positive, LA/MBC
• Official Title: A Multinational, Multicenter, Randomized, Phase 3 Study of Tesetaxel Plus a Reduced Dose of Capecitabine Versus Capecitabine Alone in Patients With HER2 Negative, HR Positive, Locally Advanced or Metastatic Breast Cancer Previously Treated With a Taxane
• Brief Summary: CONTESSA is a multinational, multicenter, randomized, Phase 3 study of tesetaxel in patients with HER2 negative, HR positive LA/MBC previously treated with a taxane in the neoadjuvant or adjuvant setting. The primary objective of the study is to compare the efficacy of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone based on progression-free survival (PFS) as assessed by the Independent Radiologic Review Committee (IRC). 685 patients were enrolled.

Detailed Description

CONTESSA is a multinational, multicenter, randomized, Phase 3 study of tesetaxel plus a reduced dose of capecitabine versus the approved dose of capecitabine alone in patients with HER2 negative, HR positive locally advanced or metastatic breast cancer (LA/MBC) previously treated with a taxane in the neoadjuvant or adjuvant setting. 685 patients were enrolled, including 674 who received treatment.

Patients randomly assigned to Arm A (tesetaxel plus a reduced dose of capecitabine) are administered:

• Tesetaxel (27 mg/m2) orally once every 21 days on Day 1 of each 21-day cycle; and
• Capecitabine (825 mg/m2) orally twice daily (in the morning and evening after a meal, for a 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.

Patients randomly assigned to Arm B (approved dose of capecitabine alone) are administered:

• Capecitabine (1,250 mg/m2) orally twice daily (in the morning and evening after a meal, for a total daily dose of 2,500 mg/m2) beginning with the evening dose on Day 1 through the morning dose on Day 15 of each 21-day cycle

Dose modifications for tesetaxel and/or capecitabine are described in the study protocol.

Patients are treated until documentation of progressive disease (PD), evidence of unacceptable toxicity or other decision to discontinue treatment. Capecitabine is an oral chemotherapy agent that is considered a standard-of-care treatment in LA/MBC. The primary efficacy endpoint is PFS as assessed by the IRC. The secondary efficacy endpoints are overall survival (OS), objective response rate (ORR) as assessed by the IRC and disease control rate (DCR) as assessed by the IRC.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Breast Cancer

Intervention

• Drug: Tesetaxel and Capecitabine
  Tesetaxel plus reduced dose of Capecitabine
• Drug: Capecitabine
  Capecitabine alone at approved dose

Study Arms

• Experimental: Arm A: Tesetaxel (oral) and capecitabine (oral)
  Tesetaxel (27 mg/m2) once every 21 days on Day 1 of each 21-day cycle; and capecitabine (825 mg/m2) twice daily (in the morning and evening after a meal, for a 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
  Intervention: Drug: Tesetaxel and Capecitabine
• Active Comparator: Arm B: Capecitabine (oral)
  Capecitabine (1,250 mg/m2) twice daily (in the morning and evening after a meal, for a total daily dose of 2,500 mg/m2) beginning with the evening dose on Day 1 through the morning dose on Day 15 of each 21-day cycle
  Intervention: Drug: Capecitabine

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: October 26, 2020): 685
• Original Estimated Enrollment (submitted: October 25, 2017): 600
• Actual Study Completion Date: June 28, 2021
• Actual Primary Completion Date: August 24, 2020 (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 (estrogen receptor [ER] and/or progesterone receptor [PgR]) positive disease based on local testing: ASCO/CAP guidelines should be utilized for assessing HR status

5. Measurable disease per RECIST 1.1 or bone-only disease with lytic component

   • Patients with bone-only metastatic cancer must have a lytic or mixed lytic-blastic lesion that can be accurately assessed by computerized tomography (CT) or magnetic resonance imaging (MRI). Patients with bone-only disease without a 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 randomization
     • 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 randomization
     • Prior stereotactic brain radiosurgery is permitted
     • CNS surgical resection must have been completed > 28 days prior to the date of randomization; patient must have complete recovery from surgery
6. Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2
7. Prior therapy (at least one completed dose) with a taxane-containing regimen in the neoadjuvant or adjuvant setting
8. Prior therapy with an anthracycline-containing regimen in the neoadjuvant, adjuvant, or metastatic setting, where indicated by local regulation or Investigator judgment.
9. 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.
10. Documented disease recurrence or disease progression of: (a) locally advanced disease that is not considered curable by surgery and/or radiation; or (b) metastatic disease.

11. 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
12. Complete recovery to baseline or Grade 1 per National Cancer Institute (NCI) 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
13. Ability to swallow an oral solid-dosage form of medication
14. 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)

15. 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 devices or double barrier methods, including male/female condoms with spermicide and use of contraceptive sponge, cervical cap, or diaphragm

16. Male patients must use an effective, non-hormonal form of contraception from screening throughout the treatment phase and until 130 days after last dose of study treatment

    • Acceptable methods include male/female condoms with spermicide, or vasectomy with medical confirmation of surgical success

17. Written informed consent and authorization to use and disclose health information
18. 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 in the metastatic setting
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. History of hypersensitivity to taxanes; hypersensitivity to the solvent does not preclude patient participation in this study
11. 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 randomization
12. Major surgery ≤ 28 days prior to the date of randomization; patient must have complete recovery from surgery
13. 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)
14. History of hypersensitivity or unexpected reactions to capecitabine, other fluoropyrimidine agents or any of their ingredients
15. 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.
16. Pregnant or breastfeeding
17. If, in the opinion of the Investigator, the patient is deemed unwilling or unable to comply with the requirements of the study
18. Treatment with brivudine, sorivudine or its chemically-related analogs ≤ 28 days prior to the date of randomization

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, Austria, Belgium, Canada, Czechia, France, Germany, Hungary, Italy, Korea, Republic of, Poland, Russian Federation, Singapore, Spain, Taiwan, Thailand, Ukraine, United Kingdom, United States

Administrative Information

• NCT Number: NCT03326674
• Other Study ID Numbers: ODO-TE-B301
• Has Data Monitoring Committee: Yes

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

• Plan to Share IPD: Undecided
• Plan Description: Currently under evaluation by the organization

• 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