Tucatinib + Abemaciclib + Herceptin for HER2+ MBC

NCT03846583 | Withdrawn Phase 1 DMC FDA Drug

• 1 other identifier: 18-621
• Study Type: interventional
• Target: N/A
• Locations: 0 countries
• Sites: N/A

Brief Summary

This research study is studying a combination of drugs as a possible treatment for HER2-Postive Metastatic Breast Cancer. The interventions involved in this study are:

• Tucatinib
• Abemaciclib (VerzenioTM)
• Trastuzumab (Herceptin®)
• Endocrine Therapy: Exemestane (Aromasin®), Letrozole (Femara®), or Anastrozole (Arimidex®)

Conditions

Breast Cancer

Keywords

Breast Cancer

Outcome Measures

Primary Outcomes (1)

• The Maximum Tolerated Dose

  Determine recommended MTD for phase 2 combination of tucatinib with abemaciclib and trastuzumab.

  2 years

Secondary Outcomes (9)

• Overall Response Rate

  20 year

• Duration of Response

  2 years

• Extracranial ORR

  2 Years

• Progression Free Survival

  2 years

• Duration of Extracranial Response

  2 Years

Study Arms (4)

Dose Escalation

EXPERIMENTAL

* Tucatinib is administered orally twice daily * Abemaciclib is administered orally twice daily * Trastuzumab is adminidtered intravenously once every three weeks * Aromatase Inhibitor is administered orally once daily

Drug: Tucatinib; Drug: Abemaciclib; Drug: Trastuzumab; Drug: Aromatase Inhibitor

Arm A: Active Brain Metastases

EXPERIMENTAL

* Tucatinib is administered orally twice daily * Abemaciclib is administered orally twice daily * Trastuzumab is adminidtered intravenously once every three weeks * Aromatase Inhibitor is administered orally once daily

Drug: Tucatinib; Drug: Abemaciclib; Drug: Trastuzumab; Drug: Aromatase Inhibitor

Arm B: Surgical Resection Needed

EXPERIMENTAL

* Tucatinib is administered orally twice daily * Abemaciclib is administered orally twice daily * Trastuzumab is adminidtered intravenously once every three weeks * Aromatase Inhibitor is administered orally once daily

Drug: Tucatinib; Drug: Abemaciclib; Drug: Trastuzumab; Drug: Aromatase Inhibitor

Arm C: Progressive Extracranial Disease

EXPERIMENTAL

* Tucatinib is administered orally twice daily * Abemaciclib is administered orally twice daily * Trastuzumab is adminidtered intravenously once every three weeks * Aromatase Inhibitor is administered orally once daily

Drug: Tucatinib; Drug: Abemaciclib; Drug: Trastuzumab; Drug: Aromatase Inhibitor

Interventions

Tucatinib DRUG

Tucatinib is a drug that inhibits human epidermal growth factor receptor 2 (HER-2) protein, which is a protein expressed in the cancer cells. By inhibiting this protein, tucatinib may help stop or reduce the growth of the tumor

Arm A: Active Brain Metastases; Arm B: Surgical Resection Needed; Arm C: Progressive Extracranial Disease; Dose Escalation

Abemaciclib DRUG

Abemaciclib is a cyclin-dependent kinase (CDK) inhibitor. CDK inhibitors work to stop cell growth.

Also known as: Verzenio

Arm A: Active Brain Metastases; Arm B: Surgical Resection Needed; Arm C: Progressive Extracranial Disease; Dose Escalation

Trastuzumab DRUG

• Trastuzumab is called a "targeted therapy" because it works by attaching itself to specific receptors on the surface of breast cancer cells, known as HER2 receptors. When Trastuzumab attaches to HER2 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the immune system.

Also known as: Herceptin

Arm A: Active Brain Metastases; Arm B: Surgical Resection Needed; Arm C: Progressive Extracranial Disease; Dose Escalation

Aromatase Inhibitor DRUG

These drugs act by lowering the amount of estrogen produced by the body by blocking an enzyme called aromatase

Arm A: Active Brain Metastases; Arm B: Surgical Resection Needed; Arm C: Progressive Extracranial Disease; Dose Escalation

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Dose Escalation Cohort:
• At least one measurable or non-measurable metastasis by radiographic evaluation or physical examination.
• Progressive breast cancer on most recent regimen
• Presence of CNS metastases allowed, but not required for participation in the dose escalation cohort.
• Expansion Cohort A:
• At least one measurable CNS metastasis per RANO-BM, defined as ≥ 10 mm in at least one dimension.
• Unequivocal evidence of new and/or progressive brain metastases, and at least one of the following scenarios:
• Treated with SRS or surgery with residual un-treated lesions remaining. Such participants are eligible for immediate enrollment on this study providing that at least one untreated lesion is measurable
• Participants who have had prior WBRT and/or SRS and then whose lesions have subsequently progressed are also eligible. In this case, lesions which have been treated with SRS may be considered as target lesions if there is unequivocal evidence, in the opinion of the treating physician, of progression following SRS.
• Participants who have not previously been treated with cranial radiation (e.g., WBRT or SRS) are eligible to enter the study, but such participants must be asymptomatic from their CNS metastases and not requiring corticosteroids for symptom control.
• Both participants who present with systemic stable/absent or systemic progressive disease are eligible, as long as they fulfill one of the above criteria.
• Expansion Cohort B:
• New and/or progressive brain metastasis(es) with clinical indication for surgical resection.
• Participants must have evaluable intracranial disease according to RANO-BM prior to surgical resection. Should participants also have extracranial disease, it may be evaluable according to RECIST 1.1
• Expansion Cohort C:

You may not qualify if:

• Visceral crisis or impending visceral crisis at time of screening.
• CNS complications for whom urgent neurosurgical intervention is indicated (e.g., resection, shunt placement).
• Known leptomeningeal metastases \[Defined as positive CSF cytology and/or unequivocal radiological evidence of clinically significant leptomeningeal involvement. CSF sampling is not required in the absence of suggestive symptoms to exclude leptomeningeal involvement\].
• Patients unable to undergo gadolinium contrast-enhanced MRI or receive IV gadolinium contrast for any reason (e.g., due to pacemaker, ferromagnetic implants, claustrophobia, extreme obesity, hypersensivity).
• Has received prior therapy with a CDK4/6 inhibitor.
• No washout is required for endocrine therapy. If a patient has been on ovarian suppression for at least 28 days prior to study entry, ccontinuation of ovarian suppression is permitted on protocol. Patients can receive a new form of endocrine therapy with one of the commercially available AIs at the time of initiation of protocol therapy.
• Subjects with a history of grade 3 or 4 allergic reactions attributed to compounds of similar biologic composition to tucatinib and/or abemaciclib or any constituent of the product(s).
• The subject has an uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association Class III or IV, active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the previous 6 months, chronic liver or renal disease, or severe malnutrition.
• The subject is pregnant or breast-feeding.1No active, second potentially life-threatening cancer. Exceptions include non-melanoma skin cancers, curatively treated in situ cancer of the cervix, DCIS, stage1/grade 1 endometrial carcinoma.
• Has had major surgery within 21 days before treatment initiation.
• Active infection requiring iv antibiotics at the time of treatment initiation.
• Symptomatic intrinsic lung disease or extensive tumor involvement of the lungs, resulting in dyspnea at rest.
• Known intolerance to trastuzumab.
• Patients may not be receiving concurrent therapy with strong inhibitors of CYP3A4 or strong inhibitors or inducers of CYP2C8. Please refer to Appendix M for a list of inhibitors and inducers. Please note that concurrent use of trimethoprim, a component of Bactrim, is prohibited per protocol. Patients who require PCP prophylaxis will need to switch to an alternative antibiotic (e.g. mepron)

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• Eli Lilly and Company: collaborator

MeSH Terms

Conditions

Breast Neoplasms

Interventions

tucatinib; abemaciclib; Trastuzumab; Aromatase Inhibitors

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Steroid Synthesis Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action; Pharmacologic Actions; Chemical Actions and Uses; Estrogen Antagonists; Hormone Antagonists; Hormones, Hormone Substitutes, and Hormone Antagonists; Physiological Effects of Drugs

Study Officials

• Jose Pablo Leone, MD

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: February 13, 2019
• First Posted: February 19, 2019
• Study Start: June 28, 2020
• Primary Completion: September 22, 2020
• Study Completion: September 22, 2020
• Last Updated: October 23, 2020

Record last verified: 2020-10

Data Sharing

• IPD Sharing: Will share
• Shared Documents: STUDY PROTOCOL, SAP, ICF
• Time Frame: Data can be shared no earlier than 1 year following the date of publication
• Access Criteria: BCH - Contact the Technology \& Innovation Development Office at www.childrensinnovations.org or email TIDO@childrens.harvard.edu BIDMC - Contact the Beth Israel Deaconess Medical Center Technology Ventures Office at tvo@bidmc.harvard.edu BWH - Contact the Partners Innovations team at http://www.partners.org/innovation DFCI - Contact the Belfer Office for Dana-Farber Innovations (BODFI) at innovation@dfci.harvard.edu MGH - Contact the Partners Innovations team at http://www.partners.org/innovation