Study to Compare Alisertib With Paclitaxel vs. Paclitaxel Alone in Metastatic or Locally Recurrent Breast Cancer

NCT02187991 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 13-033
• Study Type: interventional
• Target: 169
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of this clinical research study is to learn if the study drug, alisertib (MLN8237), in combination with chemotherapy (paclitaxel), can shrink or slow tumor growth in women with hormone receptor (HR)-positive, human epidermal growth factor receptor 2 (HER2)-negative or HR-negative, HER2-negative (triple negative) locally recurrent or metastatic breast cancer (MBC). The safety of alisertib in combination with paclitaxel will also be studied. The physical state of the patient, symptoms, changes in the size of the tumor, and laboratory findings obtained while on-study will help the research team decide if alisertib plus paclitaxel is safe and effective in patients with this type of breast cancer. Alisertib belongs to a group of drugs called Aurora kinase inhibitors. Alisertib blocks the activity of Aurora A kinase, a protein that is involved in tumor cell multiplication and survival. Aurora A kinase is expressed at higher than normal levels in many types of cancer, including breast cancer, and preclinical studies suggest that blocking the activity of this protein can lead to the death of cancer cells. Paclitaxel is a chemotherapy drug commonly used to treat many different kinds of cancer, including metastatic breast cancer. The reason to combine alisertib and paclitaxel is that in cancer therapy, combinations of drugs are often more effective as a treatment than either of the same drugs used alone.

Conditions

Breast Cancer; Breast Carcinoma; Breast Tumors; Malignant Neoplasm of Breast

Keywords

metastatic breast cancer; Human Epidermal Growth Factor Receptor 2-negative (HER2-) breast cancer; Estrogen Receptor-positive (ER+) breast cancer; Triple Negative breast cancer; alisertib; paclitaxel

Outcome Measures

Primary Outcomes (1)

• Time to Disease Progression - Tumor Response Based on RECIST 1.1 Criteria

  Measurement of tumors (sum of longest diameters) every 8 weeks for CT/MRI and photographs, and every 12 weeks for bone scan, if applicable. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions (plus an absolute increase of at least 5 mm), or a measurable increase in a non-target lesion, or the appearance of new lesions

  until disease progression (assessed by RECIST 1.1), unacceptable toxicity, death, or discontinuation from study for any other reason, up to 3 years from date of patient registration

Secondary Outcomes (1)

• Overall Survival

  up to 4 years from date of patient registration

Study Arms (4)

ER+/HER2- Paclitaxel Alone

ACTIVE COMPARATOR

Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of a 28-day cycle

Drug: Paclitaxel

ER+/HER2- Paclitaxel plus Alisertib

EXPERIMENTAL

Paclitaxel 60 mg/m2 intravenously (IV) on days 1, 8 and 15 of a 28-day cycle; Alisertib 40 mg twice a day (BID) on days 1-3, 8-10, and 15-17 of a 28-day cycle

Drug: Paclitaxel; Drug: Alisertib

Triple Negative Paclitaxel Alone

ACTIVE COMPARATOR

Paclitaxel 90 mg/m2 IV on days 1, 8 and 15 of a 28-day cycle

Drug: Paclitaxel

Triple Negative Paclitaxel plus Alisertib

EXPERIMENTAL

Paclitaxel 60 mg/m2 intravenously (IV) on days 1, 8 and 15 of a 28-day cycle; Alisertib 40 mg BID on days 1-3, 8-10, and 15-17 of a 28-day cycle

Drug: Paclitaxel; Drug: Alisertib

Interventions

Paclitaxel DRUG

either 60 mg/m2 intravenously (IV) on days 1, 8 and 15 of a 28-day cycle (on Paclitaxel plus Alisertib arm) or 90 mg/m2 IV on days 1, 8 and 15 of a 28-day cycle (on Paclitaxel Alone arm)

Also known as: Taxol, Abraxane

ER+/HER2- Paclitaxel Alone; ER+/HER2- Paclitaxel plus Alisertib; Triple Negative Paclitaxel Alone; Triple Negative Paclitaxel plus Alisertib

Alisertib DRUG

40 mg BID (twice a day) on days 1-3, 8-10, and 15-17 of a 28-day cycle

Also known as: MLN8237

ER+/HER2- Paclitaxel plus Alisertib; Triple Negative Paclitaxel plus Alisertib

Eligibility Criteria

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

You may qualify if:

• Voluntary written informed consent before performance of any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care, and signed Health Insurance Portability and Accountability Act (HIPAA) form.
• Female subject (≥18 years old), who is either:
• post-menopausal for at least one year before the screening visit, or
• surgically sterilized, or
• willing to use an acceptable method of birth control (i.e., a hormonal contraceptive, intra-uterine device, diaphragm with spermicide, or condom with spermicide) for the duration of the study.
• Metastatic or locally recurrent breast cancer with histologic confirmation (on either primary or metastatic tumor) of one of the following:
• ER+, HER2- invasive breast cancer (any progesterone receptor \[PgR\] status)
• Poorly differentiated and/or Grade 3 invasive TNBC, defined as:
• HER2 negative status (based on most recently analyzed biopsy) is defined as immunohistochemistry (IHC) status of 0, 1+ or 2+ (if IHC 2+, a negative FISH test is required, i.e., HER2 fluorescence in situ hybridization (FISH) ratio \< 2.0 with an average HER2 copy number \<4.0 signals/cell); ER-negative and PR-negative status is defined as ER and PgR \<1% nuclei positive by IHC
• Measurable disease by modified Response Evaluation Criteria in Solid Tumors (RECIST) (v1.1) or non-measurable lytic, bone-only disease (mixed blastic/lytic bone disease is allowed); if patient has bone-predominant disease with no measurable disease, there must be a lytic component to the bone metastases that is visible on plain X-ray or CT scan that can be serially followed
• Absolute neutrophil count (ANC) \> 1500/mm³, platelets \> 100,000/mm³, Hgb \> 9 g/dL. Values must be obtained without need for myeloid growth factor or platelet transfusion support within 14 days, however, erythrocyte growth factor is allowed as per published American Society of Clinical Oncology (ASCO) guidelines (available at: http://www.asco.org/quality-guidelines/asco-ash-clinical-practice-guideline-update-use-epoetin-and-darbepoetin-adult).
• Total bilirubin ≤ 1.5 x upper limit of normal (ULN), serum glutamic-oxaloacetic transaminase (SGOT) (AST) and serum glutamic-pyruvic transaminase (SGPT) (ALT) \< 2.5 x ULN. AST and/or ALT may be up to 5 x ULN if patient has known liver metastases
• Adequate renal function as defined by: Calculated creatinine clearance must be ≥ 30 mL/minute (see Cockcroft-Gault formula in Appendix 5)
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (refer to Appendix 4)

You may not qualify if:

• Previous radiation therapy covering the whole pelvis
• Suspected brain metastases, untreated brain metastases or current clinical or radiologic progression of known brain metastases or requirement for steroid therapy for brain metastases
• Patients with treated brain metastases are eligible if they have been stable and off steroids for ≥ 3 weeks
• Prior allogeneic bone marrow or organ transplantation
• Known GI disease or GI procedures that could interfere with the oral absorption or tolerance of alisertib. Examples include, but are not limited to partial gastrectomy, history of small intestine surgery, and celiac disease
• Known history of uncontrolled sleep apnea syndrome and other conditions that could result in excessive daytime sleepiness, such as severe chronic obstructive pulmonary disease; requirement for supplemental oxygen.
• Requirement for administration of proton pump inhibitor, or for constant administration of H2 antagonist, or pancreatic enzymes. Intermittent uses of antacids or H2 antagonists are allowed as described in Section 3.4.
• Systemic infection requiring IV antibiotic therapy within 14 days preceding the first dose of study drug, or other severe infection.
• Myocardial infarction within 6 months prior to enrollment or has New York Heart Association (NYHA) Class III or IV heart failure (see Appendix 3), uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities. Prior to study entry, any ECG abnormality at Screening has to be documented by the investigator as not medically relevant.
• Female subject who is pregnant or breast-feeding. Confirmation that the subject is not pregnant must be established by a negative serum B-human chorionic gonadotropin (B-hCG) pregnancy test result obtained during screening, within 72 hours prior to first dose of study drug(s). Pregnancy testing is not required for post-menopausal or surgically sterilized women.
• Patient has received an investigational agent within 30 days before enrollment
• Serious medical or psychiatric illness likely to interfere with participation in this clinical study.
• Other severe acute or chronic medical and/or psychiatric condition(s), including but not limited to uncontrolled diabetes, malabsorption, resection of the pancreas or upper small bowel, requirement for pancreatic enzymes, any condition that would modify small bowel absorption of oral medications, or laboratory abnormalities 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 not eligible for enrollment for this study.
• Diagnosed or treated for another malignancy within 3 years of enrollment, with the exception of complete resection of basal cell carcinoma or squamous cell carcinoma of the skin, or an in situ malignancy, or a stage I cancer with a 5-year Disease Free Survival (DFS) of ≥ 90% (survival rates by stage are available for most cancers on the American Cancer Society website).
• Treatment with clinically significant enzyme inducers, such as the enzyme-inducing antiepileptic drugs phenytoin, carbamazepine or phenobarbital, or rifampin, rifabutin, rifapentine or St. John's wort within 14 days prior to the first dose of alisertib and during the study.

Sponsors & Collaborators

• US Oncology Research: lead
• Millennium Pharmaceuticals, Inc.: collaborator

Study Sites (1)

22 Sites

Including Dallas and Austin, Texas, United States

Location

Related Publications (1)

• O'Shaughnessy J, McIntyre K, Wilks S, Ma L, Block M, Andorsky D, Danso M, Locke T, Scales A, Wang Y. Efficacy and Safety of Weekly Paclitaxel With or Without Oral Alisertib in Patients With Metastatic Breast Cancer: A Randomized Clinical Trial. JAMA Netw Open. 2021 Apr 1;4(4):e214103. doi: 10.1001/jamanetworkopen.2021.4103.

  PMID: 33877311 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

Paclitaxel; Albumin-Bound Paclitaxel; MLN 8237

Condition Hierarchy (Ancestors)

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

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins

Limitations and Caveats

This study has some limitations. First, poor accrual to the TN MBC cohort, likely owing to paclitaxel alone control arm, precludes reliable interpretation of the limited data obtained in this trial. In addition, ER-positive, ERBB2-negative MBC is a heterogeneous disease, and this study does not provide insight into how to identify patients who may benefit from adding alisertib to paclitaxel, as well as those who may not benefit.

Results Point of Contact

• Title: Taqi Mohammad
• Organization: Sarah Cannon Development Innovations, LLC

taqi.mohammad@scri.com

713-870-2175

Study Officials

• Joyce A. O'Shaughnessy, MD

  US Oncology Research, McKesson Specialty Health

  PRINCIPAL INVESTIGATOR

Publication Agreements

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

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 6, 2014
• First Posted: July 11, 2014
• Study Start: February 12, 2015
• Primary Completion: April 11, 2024
• Study Completion: August 1, 2024
• Last Updated: October 9, 2024
• Results First Posted: October 9, 2024

Record last verified: 2024-09

Locations

US (1)