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.

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Breast Cancer	Drug: Tesetaxel; Drug: Capecitabine	Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 152 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• 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
• Actual Study Start Date: February 5, 2019
• Actual Primary Completion Date: June 11, 2021
• Actual Study Completion Date: June 11, 2021

Arms and Interventions

Arm

Intervention/treatment

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.

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

Outcome Measures

Primary Outcome Measures :

1. ORR as assessed by the IRC [ Time Frame: Approximately 2.0-2.5 years ]

Secondary Outcome Measures :

1. DoR as assessed by the IRC [ Time Frame: Approximately 2.0-2.5 years ]
2. PFS as assessed by the IRC [ Time Frame: Approximately 2.0-2.5 years ]
3. DCR as assessed by the IRC [ Time Frame: Approximately 2.0-2.5 years ]
4. OS [ Time Frame: Approximately 3.0-3.5 years ]
5. 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 ]
6. CNS DoR as assessed by the CNS IRC in patients with CNS metastases at baseline [ Time Frame: Approximately 2.0-2.5 years ]
7. 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 ]
8. CNS OS in patients with CNS metastases at baseline or a history of CNS metastases [ Time Frame: Approximately 3.0-3.5 years ]

Other Outcome Measures:

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

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

United States, California

Innovative Clinical Research Institute

Whittier, California, United States, 90603

United States, Colorado

Rocky Mountain Cancer Center

Lakewood, Colorado, United States, 80228

United States, Florida

Sarah Cannon Research Institute - Florida Cancer Specialists

Fort Myers, Florida, United States, 33901

Florida Cancer Specialists and Research Institute

Saint Petersburg, Florida, United States, 33705

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, New York

New York Cancer and Blood Specialists

East Setauket, New York, United States, 11733

United States, Tennessee

West Cancer Center

Germantown, Tennessee, United States, 38138

United States, Texas

Texas Oncology - Baylor Charles A. Sammons Cancer Center

Dallas, Texas, United States, 75246

United States, Virginia

Virginia Oncology Associates

Norfolk, Virginia, United States, 23502

Australia, New South Wales

Border Medical Oncology

Albury, New South Wales, Australia, 2640

Canada

Hopital Maisonneuve-Rosemont

Montréal, Canada, H1T 4B3

Center Hospitalier de Montreal CHUM McPeak Sirois

Montréal, Canada, H2X 3E4

CIUSSS de Centre-Ouest-de-l'Île-de-Montréal Jewish General Hospital

Montréal, Canada, H3T IE2

McGill University Health Center

Montréal, Canada, H4J 3J1

CHU de Quebec-University Laval

Québec, Canada, G1S 4L8

Centre Hospitalier Universitaire de Sherbrooke CIUSSS de lEstrie CHUS patyre

Sherbrooke, Canada, J1H 5N4

Korea, Republic of

Kyungpook National University Hospital

Daegu, Korea, Republic of

National Cancer Center

Goyang, Korea, Republic of

Gangnam Severance Hospital

Seoul, Korea, Republic of, 06273

Asan Medical Center

Seoul, Korea, Republic of

Ajou University Hospital

Suwon, Korea, Republic of

Spain

Hospital Teresa Herrera Materno-Infantil (CHUAC)

A Coruña, Spain, 15006

Fundacion Jimenez Diaz

Madrid, Spain, 28040

Taiwan

National Taiwan University Hospital

Taipei City, Taiwan

Koo Foundation Sun Yat-Sen Cancer Center

Taipei, Taiwan

Sponsors and Collaborators

Odonate Therapeutics, Inc.

Investigators

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

More Information

• Responsible Party: Odonate Therapeutics, Inc.
• ClinicalTrials.gov Identifier: NCT03858972
• Other Study ID Numbers: ODO-TE-B201
• First Posted: March 1, 2019
• Last Update Posted: July 30, 2021
• Last Verified: July 2021

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

Keywords provided by Odonate Therapeutics, Inc.:

Tesetaxel; Capecitabine; HER2 negative; Combination of tesetaxel and capecitabine; Taxane-naive; Locally advanced or metastatic breast cancer; Hormone receptor positive; Metastatic breast cancer (MBC); Breast cancer; Central nervous system (CNS) metastases; de novo metastatic breast cancer; Oral chemotherapy; Taxane

Additional relevant MeSH terms:

Breast Neoplasms; Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Capecitabine; Antimetabolites, Antineoplastic; Antimetabolites; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents