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Testing the Addition of Copanlisib to Eribulin for the Treatment of Advanced-Stage Triple Negative Breast Cancer

Status
Temporarily Closed
Cancer Type
Breast Cancer
Trial Phase
Phase I
Phase II
Eligibility
18 Years and older, Male and Female
Study Type
Treatment
NCT ID
NCT04345913
Protocol IDs
10382 (primary)
10382
NCI-2020-02319
Study Sponsor
Yale University Cancer Center LAO

Summary

This phase I/II trial studies the side effects and best dose of copanlisib and how well it works when given together with eribulin in treating patients with triple negative breast cancer that has spread to other places in the body (advanced stage). Copanlisib stops the growth of a protein called PI3K, which is often changed in tumor cells and causes resistance to treatment. Chemotherapy drugs, such as eribulin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving copanlisib and eribulin may work better in treating advanced stage triple negative breast cancer compared to eribulin alone.

Objectives

PRIMARY OBJECTIVES:
I. To determine the safety, toxicity profile, dose limiting toxicity (DLT), maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of copanlisib hydrochloride (copanlisib) in combination with eribulin mesylate (eribulin) in metastatic triple negative breast cancer (TNBC). (Phase I)
II. To compare progression free survival (PFS) between eribulin and eribulin plus copanlisib arms in patients with metastatic TNBC treated with prior taxane and anthracycline. (Phase II)

SECONDARY OBJECTIVES:
I. To determine the objective response rate (ORR) and clinical benefit rate (CBR) of the combination. (Phase I)
II. To observe and record anti-tumor activity. (Phase I)
III. To compare the ORR, CBR (complete response [CR]+partial response [PR]+stable disease [SD] >= 24 weeks) and safety of eribulin and eribulin plus copanlisib arms. (Phase II)
IV. To compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients with tumors harboring mutations in PIK3CA/ PTEN or with loss of PTEN expression by immunohistochemistry (IHC) on baseline tumor biopsy. (Phase II)
V. To compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients with tumors lacking PIK3CA/ PTEN pathway alterations. (Phase II)
VI. To compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients with tumors harboring loss of PTEN expression by IHC in pre-treatment metastatic site (in patients with available tissue from metastatic site). (Phase II)
VII. To compare PTEN IHC results between paired archival primary tumor vs. baseline tumor biopsies. (Phase II)
VIII. To assess targeted inhibition by copanlisib and eribulin by measuring treatment induced changes in phosphorylated (phospho)-AKT (T308), phospho-AKT (S473), phospho-histone H3, and inhibition of apoptosis (cleaved caspase 3) between post-treatment tumor (C2D1-2) versus baseline. (Phase II)
IX. To compare the ORR, CBR, PFS of eribulin and eribulin plus copanlisib arms in patients with tumors harboring mutations in PIK3CA/PTEN by circulating tumor-derived deoxyribonucleic acid (ctDNA) at baseline, and potential changes over time. (Phase II)

EXPLORATORY OBJECTIVES:
I. To compare PTEN IHC results between paired baseline tumor biopsy versus at time of disease progression.
II. Assess baseline (pre-treatment) tumor tissue mutation or gene expression profiles to correlate treatment response.
III. Assess intrinsic and adaptive resistance mechanisms by analyzing pre and post treatment biopsies for gene expression and proteomic changes.
IV. Determine circulating tumor DNA (ctDNA) mutation profiles at baseline and changes in mutation profile and variant allele frequencies (VAFs) on cycle 2 day 1 (C2D1) and at disease progression compared to baseline to correlate with treatment response.
V. Assess circulating biomarkers predictive of treatment response.
VI. Assess plasma and serum proteomics and metabolomics predictive of treatment response.

OUTLINE: This is a phase I dose-escalation study of copanlisib and eribulin followed by a phase II study. Patients are randomized to 1 of 2 groups.

GROUP I: Patients receive eribulin intravenously (IV) over 2-5 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

GROUP II: Patients receive copanlisib IV over 60 minutes and eribulin IV over 2-5 minutes on days 1 and 8 or days 1 and 15. Cycles repeat every 21 or 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 3 years.

Eligibility

  1. Patients must have metastatic or unresectable carcinoma of the breast that is estrogen receptor (ER) negative (less than 10%), progesterone receptor (PR) negative (less than 10%), and HER2 negative/unamplified
  2. Patients must have had prior treatment with an anthracycline and taxane, unless contraindicated
  3. Patients must have progressed on at least one and not more than five prior chemotherapy regimens, including in the neoadjuvant, adjuvant, and metastatic settings
  4. All patients must agree to provide archival tumor material (most recent archival tumor tissue immediately prior to enrollment is strongly preferred) for research and must agree to undergo research tumor biopsy before treatment if presence of easily accessible lesions (judged by the treating physician). For patients with bone only disease, or patients without easily accessible lesions for the baseline research biopsy, availability of archival tumor material (2 x 4-5 micron section unstained slides, plus 15-20 x 10 micron section unstained slides or a tumor rich block) from previous breast cancer diagnosis or treatment is required for PTEN and PIK3CA analysis
  5. Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)
  6. Leukocytes >= 3,000/mcL
  7. Absolute neutrophil count >= 1,500/mcL
  8. Platelets >= 100,000/mcL
  9. Hemoglobin >= 8.0 g/dL
  10. Total bilirubin =< 1.5 x institutional upper limit of normal (ULN) (=< 3 x institutional ULN for patients with Gilbert syndrome)
  11. Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) / alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional ULN
  12. Lipase =< 1.5 x ULN
  13. Creatinine < 1.5 mg/dL AND glomerular filtration rate (GFR) >= 60 mL/min/1.73 m^2
  14. Partial thromboplastin time (PTT) =< 1.5 x ULN
  15. International normalized ratio (INR) =< 1.5 x ULN
  16. Patients with history of known type I or type II diabetes must have a fasting glucose level of < 120 mg/dL on at least 2 separate occasions or glycosylated hemoglobin measurement (HbA1c) < 8.5% at screening within 14 days prior to registration
  17. Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that their medication dose and INR/PTT is stable
  18. Prophylactic antiemetics may be administered according to standard practice. The routine use of standard antiemetics, including 5-HT3 blockers, such as granisetron, ondansetron, or an equivalent agent, is allowed as needed, as long as corrected QT (QTc) interval on baseline electrocardiogram (ECG) < 480 msec. The use of corticosteroids as antiemetics prior to copanlisib administration will not be allowed
  19. For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
  20. Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months are eligible for this trial provided they are on a stable regimen of anti-retroviral therapy (ART) with no medications otherwise prohibited by this protocol (e.g. drug-drug interactions)
  21. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load
  22. Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression. For patients with history of treated brain metastases, brain scans will be performed within 6 weeks of study enrollment. During study enrollment in the phase 2 portion of the study, brain MRI will be performed every 12 weeks or sooner if clinically-indicated in all patients with history of known brain metastases
  23. For phase 1 portion of the study only: patients with new or progressive brain metastases (active brain metastases) or leptomeningeal disease are eligible if the treating physician determines that immediate CNS specific treatment is not required and is unlikely to be required during the first cycle of therapy. This is not allowed for phase 2 portion of the study
  24. Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
  25. Patients with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better. Patients with history of known congestive heart failure (left ventricular ejection fraction [LVEF] < 50%) must have documented LVEF >= 50% within 12 months of study enrollment
  26. Known mutation status for PIK3CA and PTEN from archival tumor tissue analysis
  27. The effects of copanlisib on the developing human fetus are unknown. For this reason and because maternal toxicity, developmental toxicity and teratogenic effects have been observed in nonclinical studies and PI3K inhibitors as well as other therapeutic agents used in this trial are known to be teratogenic, women of child-bearing potential must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation, and for 1 month after the last dose of study medication. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately. Men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 3.5 months after completion of study treatment
  28. Ability to understand and the willingness to sign a written informed consent document. Participants with impaired decision-making capacity (IDMC) who have a legally-authorized representative (LAR) and/or family member available will also be eligible
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