AZD2281 Plus Carboplatin to Treat Breast and Ovarian Cancer

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by:
National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov Identifier:
NCT01445418
First received: September 30, 2011
Last updated: May 3, 2014
Last verified: April 2014
  Purpose

Background:

  • Carboplatin is approved by the Food and Drug Administration to treat cancer.
  • AZD2281 is an experimental drug in a class of agents called PARP inhibitors. PARP is a protein that is -involved in repairing DNA damage; PARP inhibitors interfere with that process.

Objectives:

  • To determine the optimum doses of AZD2281 and carboplatin that can safely be used in patients with breast and ovarian cancer.
  • To evaluate the response of the tumor to the drug combination and determine the side effects of the treatment.

Eligibility:

-Patients 18 years of age or older with breast or ovarian cancer who have a family history of cancer or who have a BRCA1 or BRCA2 mutation.

Design:

  • In this dose escalation study, the first small group of patients receives the smallest study doses of AZD2281 and carboplatin. Subsequent groups receive incrementally higher doses of first AZD2281 and then carboplatin as long as the preceding group has not experienced unacceptable side effects. When the highest safe dose is determined, additional patients receive that dose.
  • Patients receive treatment in 21-day cycles as follows: AZD2281 by mouth twice a day every day; carboplatin thorough a vein on day 8 of each cycle. Treatment may continue until it is no longer beneficial.
  • Evaluations during treatment include the following:
  • Physical examination 1 week after starting treatment and then every 3 weeks.
  • Blood tests weekly for the first 4 weeks of treatment and then every 3 weeks.
  • CT scans or other imaging tests such as ultrasound or MRI every 6 weeks to evaluate the tumor.

Condition Intervention Phase
Breast Cancer
Ovarian Cancer
Drug: AZ2281 + Carboplatin
Phase 1

Study Type: Interventional
Study Design: Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study With an Expansion Cohort of the PARP Inhibitor AZD2281 Combined With Carboplatin in BRCA1/2 Familial Breast and Ovarian Cancer and Sporadic Triple Negative Breast and Ovarian Cancer

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Determine the safety and toxicity of the combination of AZ2281 (KU-0059436) and carboplatin in BRCA 1/2-associated recurrent breast and ovarian cancer patients [ Time Frame: End of treatment ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Assess clinical activity of the combination; Determine biochemical changes in the poly(ADP-ribose) polymerase (PARP) and H2AX activity in mononuclear cells and in tumor in response to treatment [ Time Frame: End of treatment ] [ Designated as safety issue: No ]

Estimated Enrollment: 106
Study Start Date: March 2008
Estimated Study Completion Date: June 2015
Estimated Primary Completion Date: December 2014 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Cohort 1
Standard dose escalation: AZD2281 po bid qd + IV carboplatin D8 of each 21-day cycle.
Drug: AZ2281 + Carboplatin

Standard Dose escalation: AZD2281 po bid qd + IV carboplatin D8 of each 21-day cycle.

Expanded cohort treated at the MTD of the combination identified in Cohort 1.

Experimental: Cohort 2
Expanded cohort treated at the MTD of the combination identified in Cohort 1.
Drug: AZ2281 + Carboplatin

Standard Dose escalation: AZD2281 po bid qd + IV carboplatin D8 of each 21-day cycle.

Expanded cohort treated at the MTD of the combination identified in Cohort 1.


  Show Detailed Description

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:

Patients must have breast and/or epithelial ovarian cancer, primary peritoneal cancer, and/or fallopian tube cancer histologically or cytologically confirmed at the NCI that is metastatic or unresectable and for which standard curative measures do not exist or are no

longer effective.

All patients in cohort 1 must have measurable and/or evaluable disease.

Patients in the expansion cohort 2 must have safely biopsible disease as determine by an interventional radiologist and must agree to the first mandatory biopsy (the other two biopsies optional).

Breast cancer patients with locally advanced, unresectable disease must have been previously treated with standard therapy.

There is no limit on number of prior therapy.

Patients must be at least 6 months from their last platinum exposure.

Platinum-resistant patients may participate.

Patients with allergic reaction to platinums (up to and including grade 3 without a reaction protocol, and up to and including grade 2 in the face of pretrement, but not graduated treatment exposure) are still eligible.

Age greater than or equal to 18 years.

ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).

Life expectancy greater than 3 months.

Patients must have normal organ and marrow function as defined below:

  • hemoglobin greater than or equal to 10g/dL
  • leukocytesgreater than or equal to 3,000/mcL
  • absolute neutrophil count greater than or equal to 1,500/mcL
  • platelets greater than or equal to 100,000/mcL
  • total bilirubin less than or equal to upper limit of normal (ULN) in the absence of Gilbert s syndrome
  • AST(SGOT)/ALT(SGPT) less than or equal to 2.5 X ULN
  • creatinine clearance greater than or equal to 60 mL/min by 24-hour urine

OR

  • serum creatinine less than or equal to 1.5 mg/dl
  • corrected or Ionized Calcium less than or equal to ULN
  • potassium within normal limits

A documented deleterious BRCA 1/2 germline mutation or BRCAPRO score of greater than or equal to 30% for patients enrolling in Group A.

For patients enrolling in the sporadic serous epithelial ovarian cancer group, Group B, a negative family history (BRCAPRO score less than or equal to 20% or negative BRCA1/2 mutation test).

For patients enrolling in the triple negative breast cancer (ER-/PR- /Her2-) group, Group B, a negative family history and /or BRCAPRO score less than or equal to 10% or negative BRCA1/2 mutation test).

The effects of AZD on the developing human fetus are unknown. For this reason and because platinum agents are known to be teratogenic, men and 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. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately, Patients of child-bearing potential should continue on contraception for at least three months following the last dose of therapy on study.

Toxicities from previous cancer therapies must have recovered to grade 1 (defined by CTC 3.0). Chronic stable grade 2 peripheral neuropathy secondary to neurotoxicity from prior therapies may be considered on a case by case basis by the Principal Investigator. No patients with functional impairment due to neuropathy will be eligible for the study. Hypomagnesemia will not be considered an exclusion criteria. Magnesium levels will be monitored and replaced as clinically indicated. Ability to understand and the willingness to sign a written informed consent document.

Female patients with reproductive potential must have a negative urine or serum pregnancy test within 4 days prior to the start of the study.

EXCLUSION CRITERIA:

Patients who have had chemotherapy, biological therapy, hormonal therapy (with the exception of raloxifene or others approved for bone health) or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to entering the study.

Patients may not be receiving any other investigational agents or had them in the previous 28 days.

Patients with known brain metastases diagnosed within 1 year should be excluded from this clinical trail because of their poor prognosis and because they often develop progressive neurological dysfunction that would confound the evaluation of neurologic and other adverse events.

---Patients with brain metastases diagnosed greater than 1 year prior to study entry are eligible if they received sterilizing therapy to the CNS (resection or radiation) and have been CNS recurrence-free for a full 1-year period.

Clinically significant bleeding.

Inability to swallow pills.

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 and breast-feeding women.

HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with AZD2281. In addition, these patients are at increased risk of lethal infections when treated with marrow-suppressive therapy such as carboplatin.

Previous treatment with PARP inhibitor.

Major surgery within the past 28 days.

Patients with locally advanced breast tumors presenting for their initial therapy, or patients with local (only in breast or chest wall) recurrence only will not be eligible for this trial

For subjects in the dose-expansion cohorts, history of prior invasive malignancies within the past 5 years (with the exception of non-melanomatous skin cancers, non-invasive bladder cancer, stage I endometrial cancer or cervical cancer cured by surgical resection).

Patients with a history of grade 4 allergic reaction to platinums

  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01445418

Contacts
Contact: Nicole D. Houston, R.N. (301) 443-6431 houstonnd@mail.nih.gov
Contact: Jung-Min Lee, M.D. (301) 443-7735 leej6@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Jung-Min Lee, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Additional publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):
ClinicalTrials.gov Identifier: NCT01445418     History of Changes
Obsolete Identifiers: NCT00647062
Other Study ID Numbers: 080092, 08-C-0092
Study First Received: September 30, 2011
Last Updated: May 3, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
Genetic
BRCA
Ovarian Cancer, sporadic epithelial ovarian cancer
Breast Cancer, triple negative breast cancer
Metastatic
Breast Cancer
Ovarian Cancer

Additional relevant MeSH terms:
Breast Neoplasms
Ovarian Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Carboplatin
Antineoplastic Agents
Therapeutic Uses
Pharmacologic Actions

ClinicalTrials.gov processed this record on August 21, 2014