Cabazitaxel Plus Lapatinib as Therapy for HER2-Positive Metastatic Breast Cancer Patients With Intracranial Metastases

NCT01934894 | Terminated Phase 2 Results

• 1 other identifier: SCRI BRE 200
• Study Type: interventional
• Target: 11
• Locations: 1 country
• Sites: 4

Brief Summary

This phase II trial will combine two agents, cabazitaxel and lapatinib, to treat patients with metastatic breast cancer (MBC) which has metastasized to the brain. The first portion of the study will determine the optimal dose of the cabazitaxel/lapatinib combination to administer to patients. After determining the optimal dose, patients will continue treatment with cabazitaxel and lapatinib to assess response to treatment with these agents.

Conditions

Metastatic Breast Cancer With Intracranial Metastases

Keywords

HER2-positive breast cancer; intracranial metastases; lapatinib; cabazitaxel

Outcome Measures

Primary Outcomes (3)

• CNS Objective Response

  The number of patients with Complete and Partial Response (CR+PR) of CNS lesions assessed per modified RECIST Criteria for Evaluation of Intracranial Disease. CR=disappearance of all target and non-target lesions; PR=at least a 30% decrease in the sum of the longest diameter of target lesions, taking as reference the baseline sum longest diameter AND an absolute decrease of at least 5mm in at least one target lesion.

  every 6 weeks thru cycle 8, then every 9 weeks until treatment discontinuation, projected 1 year

• Maximum Tolerated Dose of Cabazitaxel With Lapatinib

  The maximum tolerated dose (MTD) of cabazitaxel and lapatinib will be determined as the highest dose at which ≤1 of 6 patients experiences a dose-limiting toxicity (DLT) assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0. A listing of DLTs are reported in the subsequent Primary Outcome Measure.

  weekly for 3 weeks

• Number of Participants Who Experience Dose-Limiting Toxicities (DLTs) as a Measure of Safety

  During the safety lead-in, a standard 3+3 dose escalation design is used to determine the maximum tolerated dose (MTD) of cabazitaxel with lapatinib. The MTD would be determined by the highest dose at which ≤1 of 6 patients experiences a dose-limiting toxicity (DLT) during 1 cycle (21 days) of therapy. If 2 of 6 patients within a dose level experiences a DLT, that dose level would be defined as exceeding the MTD and the previous dose level would be evaluated. DLTs are assessed according to National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.0.

  weekly for 3 weeks

Secondary Outcomes (3)

• CNS Clinical Benefit Response

  every 6 weeks thru cycle 8, and every 3 cycles thereafter until treatment discontinuation, projected 1 year

• Extra-Cranial Objective Response

  every 6 weeks for 8 cycles, then every 9 weeks until treatment discontinuation, up to 1 year

• CNS Progression Free Survival

  every 6 weeks thru cycle 8, then every 9 weeks until treatment discontinuation, projected 1 year

Study Arms (1)

cabazitaxel and lapatinib combination

EXPERIMENTAL

* Cabazitaxel 1-hour IV infusion on Day 1 of each 3 week cycle (dose to be determined) * Lapatinib PO once daily (dose to be determined) Treatment cycles will be repeated every 3 weeks.

Drug: cabazitaxel; Drug: lapatinib

Interventions

cabazitaxel DRUG

Also known as: Jevtana, XRP6258

cabazitaxel and lapatinib combination

lapatinib DRUG

Also known as: Tykerb, GW572016

cabazitaxel and lapatinib combination

Eligibility Criteria

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

You may qualify if:

• Patients with HER2-positive MBC and unequivocal evidence of brain metastases.
• Documented HER2-positive tumor status at study entry defined as:
• Immunohistochemical (IHC) score 3+ or
• IHC score 1-2+ and confirmed as FISH (Fluorescence in situ hybridization) positive (based on ASCO-CAP guidelines 2013) or
• FISH or ISH (in situ hybridization) positive (based on ASCO-CAP guidelines 2013)
• Patient must have at least one measurable brain lesion (defined as any lesion ≥ 5mm cm in the longest dimension), on T1 weighted, gadolinium enhanced MRI. Patients may have had surgical excisions of brain metastases provided at least one lesions meets the following criteria:
• Patients with brain metastases previously untreated with any intra-cranial radiation (i.e. no whole brain radiation therapy \[WBRT\]/partial brain radiation or stereotactic radiosurgery \[SRS\]) must have at least one intra-cranial tumor lesion that is ≥ 5mm.
• Patients with brain metastases previously untreated with any intracranial radiation (i.e., no whole brain radiation therapy \[WBRT\]/partial brain radiation or stereotactic radiosurgery \[SRS\]) must have at least one intracranial tumor lesion that is ≥ 5mm.
• Patients with brain metastases previously treated with WBRT/partial brain radiation only must have at least one intracranial tumor lesion ≥ 5mm and must have evidence of intracranial progressive disease
• Patients previously treated with WBRT/partial brain radiation and SRS must have at least one intracranial tumor lesion ≥ 5mm that was not treated with SRS and must have intracranial disease.
• Patients previously treated with SRS must either demonstrate disease progression ≥ 12 weeks after completing SRS with a lesion measuring ≥ 5mm or must have at least one intracranial tumor lesion ≥ 5mm that was not treated with SRS.
• Patients who have received WBRT/partial brain radiation for intra-cranial metastases are eligible if treatment was completed ≥28 days prior to the first dose of study drug.
• Estrogen receptor (ER) and progesterone receptor (PR) status in the primary or most recent tumor assessment must be known or pending at the time of study registration. Patient's ER/PR status (i.e., positive or negative) does not influence enrollment but is a requirement.
• Patient must have received prior treatment with HER2-directed therapy such as trastuzumab, either in the adjuvant or metastatic setting.
• Prior treatment with lapatinib in the (neo)adjuvant and metastatic setting.

You may not qualify if:

• Previous treatment with cabazitaxel.
• CNS disease requiring immediate neurosurgical intervention (e.g., resection, shunt placement, etc.).
• Leptomeningeal metastases as the only site of CNS metastases. Patients with parenchymal brain metastases and leptomeningeal metastases are eligible provided they meet all other eligibility criteria.
• Peripheral neuropathy ≥Grade 2 (CTCAE v4.0).
• Concurrent treatment with radiation therapy, hormonal therapy, biologic therapy or chemotherapy is not allowed. Low dose corticosteroids (≤30 mg/day prednisone or its equivalent) are allowed.
• Concurrent treatment with drugs known to be moderate and strong inhibitors or inducers of isoenzyme CYP3A that cannot be discontinued or switched to different medication prior to starting study drug.
• Concurrent use of St. John's wort and grapefruit/grapefruit juice ≤7 days prior to starting study drug is not allowed.
• Presence of active gastrointestinal (GI) disease or other condition that in the opinion of the investigator will interfere significantly with the absorption, distribution, metabolism, or excretion of oral therapy (e.g. ulcerative disease, uncontrolled nausea, or vomiting).
• Known diagnosis of human immunodeficiency virus (HIV), Hepatitis B (HBV) or Hepatitis C (HCV).
• Presence of other active cancers, or history of treatment for invasive cancer ≥3 years. Patients with stage I cancer who have received definitive local treatment with curative intent at least 3 years previously, and are considered unlikely to recur are eligible. All patients with previously treated in situ carcinoma (i.e. non-invasive) are eligible, as are patients with history of non-melanoma skin cancer.
• Any severe and/or uncontrolled medical conditions or other conditions that could affect participation in the study such as:
• Symptomatic congestive heart failure (CHF) of New York Heart Association Class III or IV.
• QTc \> 480 ms on screening ECG (using the Fredericia formula)
• Poorly controlled or clinically significant atherosclerotic vascular disease including cerebrovascular accident (CVA), transient ischemic attack (TIA), angioplasty, cardiac or vascular stenting in the past 6 months
• Active (acute or chronic) or uncontrolled severe infections.

Sponsors & Collaborators

• SCRI Development Innovations, LLC: lead
• Novartis: collaborator
• GlaxoSmithKline: collaborator
• Sanofi: collaborator

Study Sites (4)

Florida Cancer Specialists - South

Fort Myers, Florida, 33916, United States

Location

Florida Cancer Specialists-North

St. Petersburg, Florida, 33705, United States

Location

Oncology Hematology Care Inc.

Cincinnati, Ohio, 45242, United States

Location

Tennessee Oncology

Nashville, Tennessee, 37203, United States

Location

Related Publications (9)

• Cisternino S, Bourasset F, Archimbaud Y, Semiond D, Sanderink G, Scherrmann JM. Nonlinear accumulation in the brain of the new taxoid TXD258 following saturation of P-glycoprotein at the blood-brain barrier in mice and rats. Br J Pharmacol. 2003 Apr;138(7):1367-75. doi: 10.1038/sj.bjp.0705150.

  PMID: 12711638 BACKGROUND

• Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

  PMID: 19097774 BACKGROUND

• Geyer CE, Forster J, Lindquist D, Chan S, Romieu CG, Pienkowski T, Jagiello-Gruszfeld A, Crown J, Chan A, Kaufman B, Skarlos D, Campone M, Davidson N, Berger M, Oliva C, Rubin SD, Stein S, Cameron D. Lapatinib plus capecitabine for HER2-positive advanced breast cancer. N Engl J Med. 2006 Dec 28;355(26):2733-43. doi: 10.1056/NEJMoa064320.

  PMID: 17192538 BACKGROUND

• Lin NU, Winer EP. Brain metastases: the HER2 paradigm. Clin Cancer Res. 2007 Mar 15;13(6):1648-55. doi: 10.1158/1078-0432.CCR-06-2478.

  PMID: 17363517 BACKGROUND

• Lin NU, Carey LA, Liu MC, Younger J, Come SE, Ewend M, Harris GJ, Bullitt E, Van den Abbeele AD, Henson JW, Li X, Gelman R, Burstein HJ, Kasparian E, Kirsch DG, Crawford A, Hochberg F, Winer EP. Phase II trial of lapatinib for brain metastases in patients with human epidermal growth factor receptor 2-positive breast cancer. J Clin Oncol. 2008 Apr 20;26(12):1993-9. doi: 10.1200/JCO.2007.12.3588.

  PMID: 18421051 BACKGROUND

• Lin NU, Dieras V, Paul D, Lossignol D, Christodoulou C, Stemmler HJ, Roche H, Liu MC, Greil R, Ciruelos E, Loibl S, Gori S, Wardley A, Yardley D, Brufsky A, Blum JL, Rubin SD, Dharan B, Steplewski K, Zembryki D, Oliva C, Roychowdhury D, Paoletti P, Winer EP. Multicenter phase II study of lapatinib in patients with brain metastases from HER2-positive breast cancer. Clin Cancer Res. 2009 Feb 15;15(4):1452-9. doi: 10.1158/1078-0432.CCR-08-1080.

  PMID: 19228746 BACKGROUND

• Pivot X, Koralewski P, Hidalgo JL, Chan A, Goncalves A, Schwartsmann G, Assadourian S, Lotz JP. A multicenter phase II study of XRP6258 administered as a 1-h i.v. infusion every 3 weeks in taxane-resistant metastatic breast cancer patients. Ann Oncol. 2008 Sep;19(9):1547-52. doi: 10.1093/annonc/mdn171. Epub 2008 Apr 23.

  PMID: 18436520 BACKGROUND

• Villanueva C, Awada A, Campone M, Machiels JP, Besse T, Magherini E, Dubin F, Semiond D, Pivot X. A multicentre dose-escalating study of cabazitaxel (XRP6258) in combination with capecitabine in patients with metastatic breast cancer progressing after anthracycline and taxane treatment: a phase I/II study. Eur J Cancer. 2011 May;47(7):1037-45. doi: 10.1016/j.ejca.2011.01.001. Epub 2011 Feb 19.

  PMID: 21339064 BACKGROUND

• Yardley DA, Hart LL, Ward PJ, Wright GL, Shastry M, Finney L, DeBusk LM, Hainsworth JD. Cabazitaxel Plus Lapatinib as Therapy for HER2+ Metastatic Breast Cancer With Intracranial Metastases: Results of a Dose-finding Study. Clin Breast Cancer. 2018 Oct;18(5):e781-e787. doi: 10.1016/j.clbc.2018.03.004. Epub 2018 Mar 8.

  PMID: 29678476 DERIVED

MeSH Terms

Interventions

cabazitaxel; XRP6258; Lapatinib

Intervention Hierarchy (Ancestors)

Quinazolines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Heterocyclic Compounds

Limitations and Caveats

Early termination of study resulted in small number of subjects analyzed.

Results Point of Contact

• Title: Charles Davis, RAC
• Organization: SCRI Development Innovations

Charles.Davis2@scri-innovations.com

615-524-4341

Study Officials

• Denise A. Yardley, MD

  SCRI Development Innovations

  STUDY CHAIR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: GT60
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 27, 2013
• First Posted: September 4, 2013
• Study Start: May 1, 2014
• Primary Completion: February 1, 2016
• Study Completion: April 1, 2017
• Last Updated: July 2, 2017
• Results First Posted: June 2, 2017

Record last verified: 2017-06

Locations

US (4)