Tucatinib in combination with Oral Etoposide (VP16) and Trastuzumab in Patients with metastatic HER2+ Breast cancer (TUC-TOC)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Institut Curie

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

19 Dec 2023 → ongoing

Decision date (initial)

2023-06-26

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Safety, Efficacy, Pharmacogenomic, Pharmacokinetic

Evaluate the efficacy of tucatinib-oral VP16-trastuzumab by objective response rate (ORR) within the 6 first months after the start of treatment

Secondary objectives 11

1. Tolerability and safety profile of tucatinib in combination with oral VP16 and trastuzumab
2. To assess the efficacy of tucatinib in combination with oral VP16 and trastuzumab on progression free survival (PFS)
3. To assess the efficacy of tucatinib in combination with oral VP16 and trastuzumab on overall survival (OS)
4. To assess the duration of response (DoR) of tucatinib in combination with oral VP16 and trastuzumab
5. To assess the Time to Response (TTR) of tucatinib in combination with oral VP16 and trastuzumab
6. To evaluate the efficacy of tucatinib in combination with oral VP16 and trastuzumab in terms of clinical benefit rates
7. To assess health-related quality of life on tucatinib-Oral VP16-trastuzumab using the EQ-5D-5L instrument
8. To assess and compare the efficacy of tucatinib-oral VP16-trastuzumab in terms of proportion of patients alive and without progression at 6 months, Progression free survival (PFS) and Overall survival (OS) in the following predefined subgroups: - Patients who progressed on prior tucatinib-trastuzumab-capecitabine or with documented/anticipated toxicity related to capecitabine, and patients without progression or toxicity, - Patients with brain metastasis and patients without brain metastasis
9. Exploratory:To evaluate the pharmacokinetics of tucatinib and oral VP16 when administered in combination
10. Exploratory:To identify potential biomarkers of response and resistance mechanism by ctDNA analysis
11. Exploratory: To identify potential biomarkers of response including TOP2A and HER2 co amplification

Conditions and MedDRA coding

Metastatic HER2+ Breast cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. Disease progression under tucatinib-capecitabine-trastuzumab /OR / Medical contra-indication to initiate or continue capecitabine in association with tucatinib-trastuzumab (investigator’s decision based on patient medical history, DPD deficiency and/or capecitabine grade 2 toxicity or higher).
2. Age > 18 years,
3. Histologically confirmed HER2+ breast carcinoma (ASCO/CAP guidelines) with archived tumor tissue available
4. Have a life expectancy of at least 3 months
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
6. Participants must be able to swallow capsules
7. Participants must be able and willing to be available for the duration of the study and are willing to follow study procedures
8. Measurable disease, assessed by RECIST version 1
9. Patients with brain metastases are eligible: o Unless urgent treatment is required o If time since WBRT is ≥ 21 days prior to first dose of treatment, time since SRS is ≥ 7 days prior to first dose of treatment, or time since surgical resection is ≥ 28 days
10. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions
11. Left ventricular ejection fraction (LVEF) ≥ 50% (within 4 weeks before inclusion)
12. Adequate organ function (obtained within 14 days prior to treatment start) as evidenced by: o Absolute neutrophil count (ANC) ≥ 1.5 X 10^9/L o Hemoglobin (Hgb) ≥ 9 g/dL o Platelet count ≥ 100 X 10^9/L o Bilirubin ≤ 1.5 X upper limit of normal (ULN), except for patients with a documented history of Gilbert’s disease (≤ 2 X ULN) o Alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 2.5 X ULN (for patients with liver metastases ≤ 5 X ULN); o Alkaline phosphatase (AP) ≤ 3 X ULN (for patients with liver metastases, ≤ 5 X ULN);o Serum creatinine ≤ 1.5 mg/dL (133 μmol/L) or calculated creatinine clearance ≥ 50 mL/min (using Cockcroft-Gault formula)
13. If the patient is female: Women of childbearing potential (WCBP): negative serum pregnancy test. The patient must be willing to use effective methods of contraception. Patients must be postmenopausal, surgically infertile, or willing to use a physical barrier method of contraception in addition to an intrauterine device or hormonal contraception until at least 6 months after completion of study treatment, If the patient is male: Male patients must agree to use an acceptable method of contraception (e.g., condom) during the study and for 3 months after completion of investigational treatment,
14. Patients must be covered by a health insurance plan.
15. Capable of giving signed informed consent which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol.

Exclusion criteria 20

1. Have previously been treated with: a. lapatinib within 12 months of starting study treatment (except in cases where lapatinib was given for ≤ 21 days and was discontinued for reasons other than disease progression or severe toxicity) b. neratinib, afatinib, or other investigational HER2/ EGFR or HER2 TKI at any time previously (excepted for patients already under tucatinib who continue without interruption)
2. Patients who are pre-treated with tucatinib and who received a decreased dose of tucatinib (<300mg twice daily) are not eligible in the safety run-in phase
3. Have used a strong CYP3A4 or CYP2C8 inhibitor within 5 half-lives of the inhibitor, or have used a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment
4. Patients unable for any reason to undergo MRI of the brain
5. Leptomeningeal metastases or brain metastases requiring immediate symptomatic treatment or a high dose of corticosteroid therapy (≥2mg/day dexamethasone or equivalent)
6. Have poorly controlled (> 1/week) generalized or complex partial seizures, or manifest neurologic progression due to brain metastases notwithstanding CNS-directed therapy
7. Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1 at time of treatment start, with the following exceptions: a. Alopecia and neuropathy (must have resolved to ≤ Grade 2); b.Congestive Heart Failure (must have been ≤ Grade 1 in severity at the time of occurrence and must have resolved completely); c. Anemia (must have resolved to ≤ Grade 2)
8. Patients who have had a last dose of IV chemotherapy within 21 days, last dose of oral cytotoxic chemotherapy, radiotherapy, biological therapy, or investigational therapy within 14 days prior to treatment start. This does not apply to patients already under tucatinib who continue without interruption.
9. Patients who have had any major surgery within 28 days prior to inclusion
10. Have evidence within 2 years of the start of study treatment of another malignancy that required systemic treatment. This does not apply to patients already under tucatinib who continue without interruption
11. Concomitant use of other agents for the treatment of cancer or any investigational agent(s)
12. Women who are either pregnant, lactating, planning to get pregnant
13. Have a serious concomitant systemic disorder (eg, active infection or a gastrointestinal disorder causing clinically significant symptoms such as nausea, vomiting, diarrhea, or profound immune suppression) that, in the opinion of the investigator, would compromise the patient’s ability to adhere to the protocol, including but not limited to the following: (a) Have known human immunodeficiency virus (HIV) infection; (b) Active hepatitis B or C virus infection (screening required) or have other known chronic liver disease; (c) Severe renal impairment, interstitial lung disease (ILD), severe dyspnea at rest or requiring oxygen therapy, liver disease diagnosed with Child-Pugh A or higher cirrhosis or history of major surgical resection involving the stomach or small bowel, or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition resulting in clinically significant diarrhea
14. Have clinically significant cardiopulmonary disease such as: - ventricular arrhythmia requiring therapy, - uncontrolled hypertension (defined as persistent systolic blood pressure > 150 mm Hg and/or diastolic blood pressure > 100 mm Hg on antihypertensive medications), or - any history of symptomatic CHF o severe dyspnea at rest (CTCAE Grade 3 or above) due to complications of advanced malignancy, - hypoxia requiring supplementary oxygen therapy except when oxygen therapy is needed only for obstructive sleep apnea, - presence of ≥ Grade 2 QTc prolongation on screening ECG, - conditions potentially resulting in drug-induced prolongation of the QT interval or torsade de pointes: 1. Congenital or acquired long QT syndrome, 2. Family history of sudden death, 3. History of previous drug induced QT prolongation, 4. Current use of medications with known and accepted associated risk of QT prolongation
15. Have known myocardial infarction or unstable angina within 6 months prior to first dose of study treatment
16. Require therapy with warfarin or other coumarin derivatives (non-coumarin anticoagulants are allowed)
17. Have inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medication
18. Patients with altered mental status or psychiatric disorder that, in the opinion of the investigator, would preclude a valid patient informed consent.
19. Person deprived of liberty or placed under a legal protection regime with representation of the person.
20. Inability to comply with medical monitoring of the trial for geographic, social or psychological reasons

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. The objective response rate (ORR) is defined as the best response defined as complete or partial response occurring within the first 6 months of treatment, assessed by the investigators (according to RECIST v1.1 criteria)

Secondary endpoints 11

1. Serious adverse events (SAEs) and adverse events (AEs) according to NCI CTCAE v5.0, by grade and their relationship to tucatinib-Oral VP16-trastuzumab
2. Progression free survival (PFS) is defined as the time from the date of inclusion until progression per RECIST 1.1 as assessed by the investigator at local site or death due to any cause. The measure of interest is the median PFS
3. Overall survival (OS) is defined as the time from inclusion to the date of death due to any cause. The measure of interest is the median OS (if reached).
4. Duration of response (DoR) as defined as the time from the date of first documented response until date of documented progression per RECIST 1.1 as assessed by the investigator at local site or death due to any cause. The measure of interest is the median DoR
5. Time to response (TTR) as defined as the time from the start of treatment to the first ORR observed for patients who achieved a CR or PR. The measure of interest is the median TTR
6. Clinical benefit rate (CBR) is defined as the percentage of patients with CR, PR, or stable disease (SD) according to RECIST 1.1, as assessed by the investigator at the local site. The measure of interest is CBR at 24 weeks
7. The measure of interest is the mean difference in the change from baseline in EQ-5D-5L scale. Time to deterioration in pain, physical functioning, role functioning and global health status/QoL.
8. Proportion of patients alive and without progression at 6 months, Progression free survival (PFS) and Overall survival (OS) as defined above are compared between predefined subgroups: - Patients who progressed on prior tucatinib-trastuzumab-capecitabine therapy or have documented/anticipated capecitabine-related toxicity and patients without progression or toxicity. - Patient characteristics (patients with or without brain metastasis)
9. Exploratory: Pharmacokinetic assessments of oral VP16 (day 1, 14, 21) and tucatinib (day 14, 21) and will be performed in the safety run-in part (i.e.., the patients included in the first part)
10. Exploratory: Baseline ctDNA levels (C1) and change at 3 weeks (C2) and at progression (optional): amount, mutation status and expression level of cancer associated genes in ctDNA by NGS panel
11. Exploratory: TOP2A and HER2 co amplification will be performed by ShallowWGS using FFPE tumor tissue

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 5

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Institut Curie

Sponsor organisation

Institut Curie

Address

26 Rue D Ulm

City

Paris

Postcode

75005

Country

France

Scientific contact point

Organisation

Institut Curie

Contact name

François Clément BIDARD

Public contact point

Organisation

Institut Curie

Contact name

François Clément BIDARD

Third parties 1

Locations

1 EU/EEA country · 10 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 11 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications