Onalespib and Paclitaxel in Treating Patients With Advanced Triple Negative Breast Cancer

NCT02474173 | Terminated Phase 1 DMC

• 4 other identifiers: NCI-2015-00866OSU 151499876UM1CA186712
• Study Type: interventional
• Target: 31
• Locations: 1 country
• Sites: 4

Brief Summary

This phase Ib trial studies the side effects and best dose onalespib when given together with paclitaxel in treating patients with triple negative breast cancer that has spread to other places in the body and usually cannot be cured or controlled with treatment (advanced). Onalespib works by blocking proper processing of proteins that are important for cancer growth. This results in inability of these proteins to work properly. Paclitaxel kills breast cancer cells by interfering with their ability to divide. Giving onalespib together with paclitaxel may be better than giving either one alone in treating patients with breast cancer.

Conditions

Advanced Breast Carcinoma; Metastatic Breast Carcinoma; Stage III Breast Cancer AJCC v7; Stage IIIA Breast Cancer AJCC v7; Stage IIIB Breast Cancer AJCC v7; Stage IIIC Breast Cancer AJCC v7; Stage IV Breast Cancer AJCC v6 and v7; Triple-Negative Breast Carcinoma

Outcome Measures

Primary Outcomes (2)

• Recommended phase 2 dose (R2PD)

  Defined as level at which no more than 1 of 6 patients experience a dose limiting toxicity (maximum tolerated dose or \[MTD\]); or doses of the combination below MTD, if in the opinion of the investigators, lower doses are better tolerated and safer.

  Up to 28 days

• Toxicity profile of onalespib in combination with paclitaxel

  Will be based on the Common Terminology Criteria for Adverse Events (CTCAE) version (v.)5.0.

  Up to 2 years

Secondary Outcomes (5)

• Pharmacokinetic (PK) parameters of onalespib

  Pre-dose, immediately prior to end of infusion, 0.5, 1, 2, 4, 6, 8, and 24 hours after end of infusion on day -7 of course 1 and day 8 (and prior to starting paclitaxel, and immediately prior to end of infusion of paclitaxel on day 8)

• Pharmacokinetic (PK) parameters of paclitaxel

  Pre-dose, immediately prior to end of infusion, 0.5, 1, 2, 4, 6, 8, and 24 hours after end of infusion on days 1 and 8 of course 1 (and immediately prior to end of infusion of onalespib, prior to starting paclitaxel on day 8)

• Overall response rate (partial response [PR]+ complete response [CR])

  Up to 6 months

• Response duration

  From the time measurement criteria are met for complete response (CR) or partial response (PR) (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented, assessed up to 2 years

• Progression-free survival

  From study enrollment to first documented disease progression according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or death from any cause (whichever occurs first), assessed up to 2 years

Study Arms (1)

Treatment (onalespib, paclitaxel)

EXPERIMENTAL

SAFETY RUN-IN: Patients receive onalespib IV over approximately 1 hour on day -7. TREATMENT: Patients receive paclitaxel IV over 60 minutes on day 1, 8, and 15. Patients also receive onalespib IV over 1 hour beginning on days 8 and 15 of cycle 1 and on days 1, 8, and 15 of subsequent cycles. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis; Drug: Onalespib; Drug: Paclitaxel; Other: Pharmacological Study

Interventions

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (onalespib, paclitaxel)

Onalespib DRUG

Given IV

Also known as: AT 13387, AT-13387, AT13387

Treatment (onalespib, paclitaxel)

Paclitaxel DRUG

Given IV

Also known as: Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat

Treatment (onalespib, paclitaxel)

Pharmacological Study OTHER

Correlative studies

Treatment (onalespib, paclitaxel)

Eligibility Criteria

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

You may qualify if:

• Patients must have histologically confirmed measurable or unmeasurable advanced or metastatic breast cancer for which standard curative measures do not exist or are no longer effective
• Measurable disease is defined as at least one lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as \>= 20 mm (\>= 2 cm) with conventional techniques or as \>= 10 mm (\>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam
• Primary and/or metastatic breast tumor must be negative for over-expression of estrogen and progesterone receptors; patients with weak estrogen receptor and/or progesterone receptor expression (\< 10% on immunohistochemistry \[IHC\]) will be eligible
• Primary and/or metastatic breast tumor must be negative for human epidermal growth factor receptor (HER-2/neu) over-expression based on immunohistochemistry (IHC) (0 or 1+, 2+ if fluorescence in-situ hybridization \[FISH\] test is negative) or FISH (HER2/copy number of centromere of chromosome 17 \[CEP17\] ratio \< 2.0 or \< 4 Her-2/neu signals per nucleus)
• Any number of prior therapies for metastatic breast cancer is allowed; patients with weakly estrogen receptor positive breast cancer who received any number of endocrine agents for metastatic breast cancer will also be eligible
• Prior taxane is allowed (as long as the patient is not experiencing grade \> 1 neuropathy and had no history of disease progression on a taxane therapy within 3 months prior to study enrollment)
• Eastern Cooperative Oncology Group (ECOG) performance status =\< 2 (Karnofsky \>= 60%)
• Life expectancy of greater than 12 weeks
• Leukocytes \>= 2,000/uL
• Absolute neutrophil count \>= 1,500/uL
• Platelets \>= 100,000/uL
• Total bilirubin less than or equal to the institution's upper limit of normal
• Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) =\< 2.5 x institutional upper limit of normal (except for patients with liver metastases in whom AST/ALT can be \< 5 x institutional upper limit of normal)
• Creatinine within normal institutional limits OR creatinine clearance \>= 50 mL/min for patients with creatinine levels above institutional normal
• Left ventricular ejection fraction of \> 50% on baseline echocardiography or multi-gated acquisition (MUGA) scan

You may not qualify if:

• Patients who have had chemotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study
• Patients who are receiving any other investigational agents within 4 weeks or 5 half-lives (whichever is shorter) prior to the first dose of the study regimen
• Prior radiation therapy within 2 weeks prior to the first dose of the study regimen
• Patients in whom prior treatment related toxicities have not recovered to grade 1 or less (except for alopecia)
• Recent initiation of bone modifying therapy with a bisphosphonate or denosumab unless it has been started more than 4 weeks prior to the first dose of the study regimen; patients who are already enrolled in this study can initiate bone modifying therapy after the first set of re-staging scans (\>= 8 weeks from cycle 1, day 1)
• Prior therapy with AT13387 or another HSP90 inhibitor
• Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events; however, patients with previously treated and stable brain metastases are eligible as long as they are no longer requiring steroids, completed radiation therapy more than 2 weeks prior to the first dose of study regimen and have no seizures or worsening neurologic symptoms
• History of grade 3-4 immediate hypersensitivity reaction to paclitaxel
• History of clinically significant allergic reactions attributed to compounds of similar chemical or biologic composition to AT13387 or paclitaxel
• Based on investigator's brochure, AT13387 has no significant effects on inhibition or activation of cytochrome P450 (CYP), including 1A2, 3A4, 2D6, 2C9, and 2C19 at the half maximal inhibitory concentration (IC50) \> 10 uM. Preclinical studies indicated that AT13387 is only a modest inhibitor of P-glycoprotein (P-gp). Paclitaxel is a substrate of CYP2C8 and CYP3A4. The use of CYP2C8 and CYP3A4 inhibitors/inducers while not prohibited in this study, is discouraged whenever feasible; concurrent use of strong CYP2C8 and CYP3A4 inhibitors/inducers should be documented and the principal investigator (PI) of the study shall be notified prior to dosing; as part of the enrollment/informed consent procedures, the patients will be counseled on the risk of interactions with other agents, and what to do if new medications need to be prescribed or if the patient is considering a new over-the-counter medicine or herbal product
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Pregnant women are excluded from this study because paclitaxel is a class D agent with the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AT13387 and paclitaxel, breastfeeding should be discontinued if the mother is treated with AT13387 and paclitaxel
• Patients who are human immunodeficiency virus (HIV) positive on highly active anti-retroviral therapy (HAART) will be excluded from the study because of the potential for pharmacokinetic interactions with AT13387; in addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy; appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated
• Inability to understand and sign informed consent
• Any other medical or psychiatric condition that in the opinion of the investigator would make the study therapy unsafe for the patient

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (4)

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Thomas Jefferson University Hospital

Philadelphia, Pennsylvania, 19107, United States

Location

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

Location

Related Publications (1)

• Williams NO, Quiroga D, Johnson C, Brufsky A, Chambers M, Bhattacharya S, Patterson M, Sardesai SD, Stover D, Lustberg M, Noonan AM, Cherian M, Bystry DM, Hill KL, Chen M, Phelps MA, Grever M, Stephens JA, Ramaswamy B, Carson WE 3rd, Wesolowski R. Phase Ib study of HSP90 inhibitor, onalespib (AT13387), in combination with paclitaxel in patients with advanced triple-negative breast cancer. Ther Adv Med Oncol. 2023 Dec 25;15:17588359231217976. doi: 10.1177/17588359231217976. eCollection 2023.

  PMID: 38152697 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Triple Negative Breast Neoplasms

Interventions

(2,4-dihydroxy-5-isopropylphenyl)-(5-(4-methylpiperazin-1-ylmethyl)-1,3-dihydroisoindol-2-yl)methanone; Paclitaxel; Taxes

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; Economics; Health Care Economics and Organizations

Study Officials

• Robert Wesolowski

  Ohio State University Comprehensive Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: June 15, 2015
• First Posted: June 17, 2015
• Study Start: January 15, 2016
• Primary Completion: October 26, 2022
• Study Completion: October 26, 2022
• Last Updated: November 4, 2022

Record last verified: 2022-11

Locations

US (4)