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Olaparib and Onalespib in Treating Patients With Solid Tumors That Are Metastatic or Cannot Be Removed by Surgery or Recurrent Ovarian, Fallopian Tube, Primary Peritoneal, or Triple-Negative Breast Cancer

This study is currently recruiting participants.
Verified November 2017 by National Cancer Institute (NCI)
Sponsor:
ClinicalTrials.gov Identifier:
NCT02898207
First Posted: September 13, 2016
Last Update Posted: December 12, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
  Purpose
This phase I trial studies the side effects and best dose of olaparib and onalespib when given together in treating patients with solid tumors that have spread to other places in the body or cannot be removed by surgery or ovarian, fallopian tube, primary peritoneal, or triple-negative breast cancer that has come back. Olaparib and onalespib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Condition Intervention Phase
Estrogen Receptor Negative HER2/Neu Negative High Grade Fallopian Tube Serous Adenocarcinoma High Grade Ovarian Serous Adenocarcinoma Metastatic Malignant Solid Neoplasm Primary Peritoneal High Grade Serous Adenocarcinoma Progesterone Receptor Negative Recurrent Breast Carcinoma Recurrent Fallopian Tube Carcinoma Recurrent Ovarian Carcinoma Recurrent Primary Peritoneal Carcinoma Triple-Negative Breast Carcinoma Unresectable Solid Neoplasm Other: Laboratory Biomarker Analysis Drug: Olaparib Drug: Onalespib Other: Pharmacological Study Phase 1

Study Type: Interventional
Study Design: Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1 Study of PARP Inhibitor Olaparib and HSP90 Inhibitor AT13387 for Treatment of Advanced Solid Tumors With Expansion in Patients With Recurrent Epithelial Ovarian, Fallopian Tube, Peritoneal Cancer, or Recurrent Triple-Negative Breast Cancer

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Maximum tolerated dose defined as the highest dose at which 0 of 3 or 1 of 6 or fewer patients experience a dose-limiting toxicity [ Time Frame: Up to 35 days ]
    Based on the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0.


Other Outcome Measures:
  • Change in BRCA1 foci in tumor tissue assessed by immunohistochemistry [ Time Frame: Baseline to course 0 day 7 ]
    Paired t-tests will be used to compare BRCA1 foci formation following olaparib.

  • Change in BRCA1 foci in tumor tissue assessed by immunohistochemistry [ Time Frame: Baseline to course 1 day 15 ]
    Paired t-tests will be used to compare BRCA1 foci formation following olaparib and onalespib.

  • Change in heat shock protein (HSP)90 [ Time Frame: Baseline up to 2 years ]
    Pearson correlation coefficients, presented with 95% confidence intervals, will be used to investigate the association of the percent change HS90 activities with pharmacokinetic (PK) parameters, including maximum concentration (Cmax) and area under the curve (AUC).

  • Change in heat shock protein 70 (HSP)70 expression in tumor tissue assessed by immunohistochemistry [ Time Frame: Course 0 day 7 to course 1 day 15 ]
    Changes in parameters of HSP70 activities that occur post-treatment will be summarized using descriptive statistics.

  • Change in PARP activities [ Time Frame: Baseline up to 2 years ]
    Pearson correlation coefficients, presented with 95% confidence intervals, will be used to investigate the association of the percent change of PARP activities with PK parameters, including Cmax and AUC.

  • Change in RAD51 foci in tumor tissue assessed by immunohistochemistry [ Time Frame: Baseline to course 0 day 7 ]
    Paired t-tests will be used to compare RAD51 foci formation following olaparib.

  • Change in RAD51 foci in tumor tissue assessed by immunohistochemistry [ Time Frame: Baseline to course 1 day 15 ]
    Paired t-tests will be used to compare RAD51 foci formation following olaparib and onalespib.


Estimated Enrollment: 40
Actual Study Start Date: May 19, 2017
Estimated Study Completion Date: June 1, 2020
Estimated Primary Completion Date: June 1, 2020 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Treatment (olaparib and onalespib)
Patients receive olaparib PO BID on days 1-7 (course 0). Beginning in course 1, patients receive olaparib PO BID on days 1-28 and onalespib IV over 1 hour on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Olaparib
Given PO
Other Names:
  • AZD2281
  • KU-0059436
  • Lynparza
  • PARP Inhibitor AZD2281
Drug: Onalespib
Given IV
Other Names:
  • AT 13387
  • AT-13387
  • AT13387
Other: Pharmacological Study
Correlative studies

  Hide Detailed Description

Detailed Description:

PRIMARY OBJECTIVES:

I. To establish the maximum tolerated dose (MTDs) of olaparib and onalespib (AT13387) administered in combination in patients with advanced solid tumors.

SECONDARY OBJECTIVES:

I. To identify the dose-limiting toxicity (DLT) and other toxicities associated with olaparib and AT13387 administered in combination as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v)4.0.

II. To determine the recommended phase 2 doses (RP2D) of the combination of olaparib and AT13387.

III. To determine the plasma pharmacokinetics of olaparib and AT13387. IV. To document anti-tumor activity of the combination of olaparib and AT13387 as assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 and progression free survival (PFS).

TERTIARY OBJECTIVES:

I. To test the hypothesis that there will be induction of BRCA1 and RAD51 foci after olaparib alone and reduced formation of these foci after the combination of AT13387 and olaparib, assessed immunohistochemically.

II. To assess downregulation of expression of HR pathway genes after the combination of AT13387 and olaparib.

III. To assess whether there is induction of BRCA1 and RAD51 foci after olaparib alone assessed immunohistochemically in the optional biopsy performed after olaparib alone compared to the optional baseline biopsy prior to initiation of the study.

IV. To assess whether there is reduction of BRCA1 and RAD51 foci after the combination of olaparib and AT13387 assessed immunohistochemically in the optional biopsy performed after one of the combination olaparib and AT13387 doses (compared to the optional biopsy after olaparib alone).

V. To assess whether there is induction of HSP70 (a known biomarker of HSP90 inhibition) after the combination of olaparib and AT13387 assessed immunohistochemically in the optional biopsy performed after one of the combination olaparib and AT13387 doses (compared to the optional biopsy after olaparib alone).

VI. To assess whether there is downregulation of expression of HR pathway genes after the combination of AT13387 and olaparib assessed by Nanostring in the optional biopsy performed after one of the combination olaparib and AT13387 doses (compared to the optional biopsy after olaparib alone).

VII. To assess whether there is induction of phosphorylation (phospho) H2AX after the combination of AT13387 and olaparib assessed by immunohistochemistry in the optional biopsy performed.

VIII. To assess whether there is downregulation of CCNE1 after the combination of AT13387 and olaparib assessed by immunohistochemistry in the optional biopsy performed.

OUTLINE: This is a dose-escalation study.

Patients receive olaparib orally (PO) twice daily (BID) on days 1-7 (course 0). Beginning in course 1, patients receive olaparib PO BID on days 1-28 and onalespib intravenously (IV) over 1 hour on days 1, 2, 8, 9, 15, and 16. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and every 3 months for up to 2 years.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • For the dose escalation cohort, patients must have histologically or cytologically confirmed malignancy that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are no longer effective
  • For the dose escalation cohort, patients may have received any number of prior therapies
  • For the dose expansion cohort, participants must have histologically or cytologically confirmed diagnosis of either:

    • Ovarian, fallopian tube, or primary peritoneal cancer of high grade serous histology which has recurred despite standard therapy; up to 3 prior lines in the platinum resistant setting (i.e. up to 3 lines after patients have become platinum resistant); patients may have received unlimited lines while platinum sensitive
    • Triple-negative breast cancer (TNBC) which has recurred despite standard therapy; recurrent TNBC needs to have metastatic disease and patients with an in breast recurrence are not eligible; up to 4 prior lines in the recurrent setting for patients with triple-negative breast cancer are allowed
  • For the dose expansion cohort, patients with ovarian, fallopian tube or primary peritoneal cancer must have platinum resistant disease defined as progression within 6 months after last platinum regimen; platinum refractory disease is allowed
  • For the dose expansion cohort, patients with triple-negative breast cancer may not be BRCA1/2 germline mutation carriers
  • There must be availability of a formalin-fixed, paraffin-embedded tumor specimen
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 (Karnofsky > 60%)
  • Life expectancy of greater than 12 weeks
  • Leukocytes >= 3,000/mcL
  • Hemoglobin >= 10 g/dL with no blood transfusion in the past 28 days
  • Absolute neutrophil count >= 1,500/mcL
  • Platelets >= 100,000/mcL
  • Total bilirubin within normal institutional limits
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x institutional upper limit of normal
  • Creatinine =< the institutional upper limit of normal OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal
  • Corrected QT (QTc) =< 450 ms
  • Any clinically significant electrolyte imbalance, particularly hypokalemia and hypomagnesemia, should be corrected before treatment
  • Pre-study evaluation must include an ophthalmologic exam by an ophthalmologist (not optometrist) and should minimally include visual acuity testing, slit lamp examination, and funduscopic examination; follow up eye-exams will only be performed if subjects develop/report any visual impairment; visual impairment may include peripheral flashes (photopsia), blurred or double vision, floaters, color distortion and dimness, difficulties with light/dark accommodation, tunnel vision or other field defects, halos, apparent movement of stationary objects, and complex disturbances; follow up eye-exams will minimally include visual acuity testing, slit lamp examination, and funduscopic examination; additional testing will be based on symptoms, what is observed and ophthalmologist recommendations
  • For the expansion cohort only: measurable disease by RECIST v1.1 with at least one measurable target lesion
  • Women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry, for the duration of study participation, and for 3 months after the last dose of study drugs; 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 4 months after completion of olaparib and/or AT13387 administration
  • Patients must be able to swallow tablets and have no significant impairment in gastrointestinal absorption
  • Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

  • Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier
  • All acute, clinically significant treatment-related toxicity from prior therapy, except for alopecia, must have resolved to grade =< 1
  • Patients who are receiving any other investigational agents
  • Patients with known active or history of brain metastases should be excluded from this clinical trial
  • History of allergic reactions attributed to compounds of similar chemical or biologic composition to olaparib and AT13387 used in study
  • 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; breastfeeding should be discontinued if the mother is treated with olaparib or AT13387
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible
  • Known history of QT/QTc prolongation or torsades de pointes (TdP); patients who are currently receiving treatment with medication with a known risk to prolong the QT interval or inducing torsades de pointes and the treatment cannot either be discontinued or switched to a different medication prior to starting study drugs
  • Participants receiving any medications or substances that are strong inhibitors or inducers of CYP3A4 or moderate inhibitors of CYP3A4 are ineligible; the study team should check a frequently-updated medical reference for a list of drugs to avoid or minimize use of; as part of the enrollment/informed consent procedures, the patient 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
  • Participants with myelodysplastic syndrome/acute myeloid leukemia or with features suggestive of myelodysplastic syndrome (MDS)/acute myeloid leukemia (AML)
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02898207


Locations
United States, Arizona
Mayo Clinic in Arizona Recruiting
Scottsdale, Arizona, United States, 85259
Contact: Andrea E. Wahner Hendrickson    855-776-0015      
Principal Investigator: Andrea E. Wahner Hendrickson         
United States, Florida
Mayo Clinic in Florida Recruiting
Jacksonville, Florida, United States, 32224-9980
Contact: Andrea E. Wahner Hendrickson    855-776-0015      
Principal Investigator: Andrea E. Wahner Hendrickson         
United States, Massachusetts
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Panagiotis A. Konstantinopoulos    877-442-3324      
Principal Investigator: Panagiotis A. Konstantinopoulos         
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Panagiotis A. Konstantinopoulos    877-442-3324      
Principal Investigator: Panagiotis A. Konstantinopoulos         
Dana-Farber - Harvard Cancer Center LAO Recruiting
Boston, Massachusetts, United States, 02115
Contact: Panagiotis A. Konstantinopoulos    877-442-3324      
Principal Investigator: Panagiotis A. Konstantinopoulos         
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Panagiotis A. Konstantinopoulos    877-442-3324      
Principal Investigator: Panagiotis A. Konstantinopoulos         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Panagiotis A. Konstantinopoulos    877-442-3324      
Principal Investigator: Panagiotis A. Konstantinopoulos         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: Andrea E. Wahner Hendrickson    855-776-0015      
Principal Investigator: Andrea E. Wahner Hendrickson         
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Panagiotis Konstantinopoulos Dana-Farber - Harvard Cancer Center LAO
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02898207     History of Changes
Other Study ID Numbers: NCI-2016-01364
NCI-2016-01364 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
17-715
10031 ( Other Identifier: Dana-Farber - Harvard Cancer Center LAO )
10031 ( Other Identifier: CTEP )
UM1CA186709 ( U.S. NIH Grant/Contract )
First Submitted: September 12, 2016
First Posted: September 13, 2016
Last Update Posted: December 12, 2017
Last Verified: November 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma
Neoplasms
Adenocarcinoma
Triple Negative Breast Neoplasms
Breast Neoplasms
Ovarian Neoplasms
Fallopian Tube Neoplasms
Cystadenocarcinoma, Serous
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms by Site
Breast Diseases
Skin Diseases
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Fallopian Tube Diseases
Cystadenocarcinoma
Neoplasms, Cystic, Mucinous, and Serous
Olaparib
Poly(ADP-ribose) Polymerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents