AZD2281 Plus Carboplatin to Treat Breast and Ovarian Cancer

NCT01445418 | Completed Phase 1 FDA Drug

• 2 other identifiers: 08009208-C-0092
• Study Type: interventional
• Target: 103
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

Breast Cancer; Ovarian Cancer

Keywords

Genetic; BRCA; Ovarian Cancer, sporadic epithelial ovarian cancer; Breast Cancer, triple negative breast cancer; Metastatic; Breast Cancer; Ovarian Cancer

Outcome Measures

Primary Outcomes (1)

• Safety/Toxicity

  Determine the safety and toxicity of the combination of AZD2281 (KU- 0059436) and carboplatin in recurrent BRCA1/2-associated or familial breast and ovarian cancer patients, in recurrent low genetic risk serous ovarian cancer patients, and in recurrent low genetic risk triple negative breast cancer patients.

  End of treatment

Secondary Outcomes (1)

• 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

  End of treatment

Study Arms (2)

Arm 1

EXPERIMENTAL

Standard dose escalation

Drug: AZ2281 + Carboplatin

Arm 2

EXPERIMENTAL

Expanded cohort

Drug: AZ2281 + Carboplatin

Interventions

AZ2281 + Carboplatin DRUG

Cohort 1: Dose escalation: AZD2281 po bid qd + IV carboplatin D8 of each 21-day cycle.; Cohort 2: Expanded cohort treated at the MTD of the combination identified in Cohort 1.

Arm 1; Arm 2

Eligibility Criteria

• Age: 18 Years - 100 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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

You may not qualify if:

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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Alderson T. New targets for cancer chemotherapy--poly(ADP-ribosylation) processing and polyisoprene metabolism. Biol Rev Camb Philos Soc. 1990 Nov;65(4):623-41. doi: 10.1111/j.1469-185x.1990.tb01240.x. No abstract available.

  PMID: 2124932 BACKGROUND

• Audebert M, Salles B, Calsou P. Involvement of poly(ADP-ribose) polymerase-1 and XRCC1/DNA ligase III in an alternative route for DNA double-strand breaks rejoining. J Biol Chem. 2004 Dec 31;279(53):55117-26. doi: 10.1074/jbc.M404524200. Epub 2004 Oct 21.

  PMID: 15498778 BACKGROUND

• Berger NA, Adams JW, Sikorski GW, Petzold SJ, Shearer WT. Synthesis of DNA and poly(adenosine diphosphate ribose) in normal and chronic lymphocytic leukemia lymphocytes. J Clin Invest. 1978 Jul;62(1):111-8. doi: 10.1172/JCI109094.

  PMID: 659624 BACKGROUND

• Shamseddine AI, Farhat FS. Platinum-based compounds for the treatment of metastatic breast cancer. Chemotherapy. 2011;57(6):468-87. doi: 10.1159/000334093. Epub 2012 Jan 10.

  PMID: 22248721 DERIVED

MeSH Terms

Conditions

Breast Neoplasms; Ovarian Neoplasms; Triple Negative Breast Neoplasms; Neoplasm Metastasis

Interventions

Carboplatin

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Coordination Complexes; Organic Chemicals

Study Officials

• Jung-Min Lee, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: September 30, 2011
• First Posted: October 3, 2011
• Study Start: May 12, 2008
• Primary Completion: September 2, 2014
• Study Completion: October 18, 2019
• Last Updated: October 22, 2019

Record last verified: 2019-10-18

Locations

US (1)