CISPLATIN + AZD-1775 In Breast Cancer

NCT03012477 | Completed Phase 2 Results DMC FDA Drug

• 1 other identifier: 16-264
• Study Type: interventional
• Target: 34
• Locations: 1 country
• Sites: 1

Brief Summary

This research study is studying a combination of drugs as a possible treatment for triple-negative breast cancer that has spread to other areas of the body. The names of the study interventions involved in this study are:

• Cisplatin
• AZD1775

Conditions

Triple-negative Metastatic Breast Cancer

Keywords

Triple-negative metastatic breast cancer

Outcome Measures

Primary Outcomes (1)

• Objective Response Rate

  The objective response rate (ORR) was defined as the percentage of participants achieving complete response (CR) or partial response (PR) based on RECIST 1.1 criteria on treatment. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete response/stable disease (SD) for the evaluation of non-target lesions and absence of new lesions.

  Evaluated every 6 weeks from the time of their first treatment, per RECIST 1.1. Duration of therapy will depend on individual response, evidence of disease progression and tolerance, up to 1 year

Secondary Outcomes (6)

• Median Progression-free Survival (PFS)

  From date of initiation of study treatment until the date of first documented progression or date of death from any cause, whichever came first (approximately 3 years and 11 months ).

• Change in pCDC2 After Therapy With AZD1775 in Paired Biopsies

  Biopsies will occur 5-48 hours after the C1D1 cisplatin dose (ie. C1D2or C1D3) and 5-8hrs (+/- 24hrs) after the last dose of AZD1775 on C2D3

• Number of p53 Mutations

  Biopsies will occur 5-48 hours after the C1D1 cisplatin dose (ie. C1D2or C1D3) and 5-8hrs (+/- 24hrs) after the last dose of AZD1775 on C2D3

• Number of of BRCA1/2 Mutation

  Biopsies will occur 5-48 hours after the C1D1 cisplatin dose (ie. C1D2or C1D3) and 5-8hrs (+/- 24hrs) after the last dose of AZD1775 on C2D3

• Number of Patients Have Changes in Markers for DNA Damage

  Biopsies will occur 5-48 hours after the C1D1 cisplatin dose (ie. C1D2or C1D3) and 5-8hrs (+/- 24hrs) after the last dose of AZD1775 on C2D3

Study Arms (1)

cisplatin + AZD1775

EXPERIMENTAL

Treatment will consist of one cycle of cisplatin monotherapy (cisplatin 75 mg/m2 IV x1) followed by combination therapy of AZD1775 plus cisplatin starting 21 days(1 cycle) later. AZD1775 will be administered 200 mg as twice daily oral dosing predetermined dosing schedule, in combination with Cisplatin predetermined dosage every 21 days. At least 10 patients will undergo a research biopsy within 5-48 hours after beginning cisplatin (Cycle 1 Day 1) and then again within 5-8 hours after the last dose of AZD1775 in cycle 2 (Cycle 2 Day 3).

Drug: Cisplatin; Drug: AZD1775

Interventions

Cisplatin DRUG

chemotherapy

Also known as: Platinol

cisplatin + AZD1775

AZD1775 DRUG

Wee1 tyrosine kinase inhibitor

cisplatin + AZD1775

Eligibility Criteria

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

You may qualify if:

• Participants must have histologically or cytologically confirmed invasive breast cancer, with stage IV disease. Patients without pathologic or cytologic confirmation of metastatic disease should have unequivocal evidence of metastasis from physical examination or radiologic evaluation.
• Either the primary invasive tumor and/or the metastasis must be triple-negative, defined as:
• hormone-receptor poor, ER- and PR-negative, or staining present in \<1% by immunohistochemistry (IHC)
• HER2-negative: 0 or 1+ by IHC, or FISH\<2.0
• Participants must have at least one lesion that is not within a previously radiated field that is measurable on computerized tomography (CT) or magnetic resonance imaging (MRI) scan per RECIST version 1.1. Bone lesions are not considered measurable by definition. See Section 11 for the evaluation of measurable disease.
• Prior chemotherapy: Patients may have received 0-1 prior chemotherapeutic regimen for metastatic breast cancer and must have been off treatment with chemotherapy for at least 21 days before enrollment in the study. The number of patients with 0 prior chemotherapeutic regimen will be limited to a maximum of n = 20.
• Prior biologic therapy: Patients must have discontinued all biologic therapy at least 21 days before participation.
• Prior radiation therapy: Patients may have received prior radiation therapy in either the metastatic or early-stage setting. Radiation therapy must be completed at least 14 days prior to study participation and patients should have recovered from adverse effects of radiation to grade ≤1.
• Age ≥18
• ECOG performance status ≤1
• Participants must have normal organ and marrow function as defined below:
• Absolute neutrophil count ≥ 1500/mm3
• Platelets ≥100,000/mm3
• Hemoglobin ≥ 9 g/dL
• Total Bilirubin ≤ 1.5 mg/dL

You may not qualify if:

• Participants who are receiving any other investigational agents within 21 days of the first dose of study drug.
• Major surgical procedures \<28 days from beginning study treatment.
• Participants who have received a prior inhibitor of Wee1 kinase activity
• Participants who have received prior platinum chemotherapy
• Known brain metastases that are untreated, symptomatic, or require therapy to control symptoms. Patients with a history of treated central nervous system (CNS) metastases are eligible. Treated brain metastases are defined as those having no evidence of progression for ≥ 1 month after treatment, or hemorrhage for ≥ 2 weeks after treatment and no ongoing requirement for corticosteroids, as ascertained by clinical examination and brain imaging (magnetic resonance imaging or CT scan) during the screening period. Any corticosteroid use for brain metastases must have been discontinued without the subsequent appearance of symptoms for ≥2 weeks before the first study drug. Treatment for brain metastases may include whole brain radiotherapy, radiosurgery, or a combination as deemed appropriate by the treating physician. Patients with CNS metastases treated by neurosurgical resection or brain biopsy performed within 1 month before day 1 of study treatment will be excluded.
• Patients with grade \>1 neuropathy or grade \>1 toxicity (except alopecia or anorexia) from prior therapy
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to AZD1775 or Cisplatin.
• Participants receiving any medications, substances, or foods (ie, grapefruit juice) listed below are ineligible (Please refer to Section 5.4 for list of restricted co-medications):
• prescription or non-prescription drugs or other products known to be sensitive CYP3A4 substrates or CYP3A4 substrates with a narrow therapeutic index, or to be moderate to strong inhibitors/inducers of CYP3A4 which cannot be discontinued 2 weeks prior to Day 1 of dosing and withheld throughout the study until 2 weeks after the last dose of study drug. sensitive substrates of CYP2C8, CYP2C9, CYP2C19, or substrates of these enzymes with narrow therapeutic range
• inhibitors or substrates of P-gp
• Participants who have an uncontrolled intercurrent illness, including, but not limited to, ongoing or active infection, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, congestive heart failure-New York Heart Association Class III or IV (Appendix B), active ischemic heart disease, myocardial infarction within the previous six months, uncontrolled diabetes mellitus, gastric or duodenal ulceration diagnosed within the previous 6 months, chronic liver or renal disease, or severe malnutrition. In addition, patients are ineligible if they have a psychiatric illness or a social situation that could limit their ability to comply with the study requirements.
• Participants who have refractory nausea and vomiting, chronic gastrointestinal diseases, or previous significant bowel resection that would preclude adequate absorption of AZD1775.
• Pregnant women are excluded from this study because AZD1775 is a Wee1 inhibitor agent with the potential for teratogenic or abortifacient effects.
• Lactating or breastfeeding women are excluded because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD1775, breastfeeding should be discontinued prior to being treated with AZD1775. These potential risks may also apply to other agents used in this study.
• Known HIV-positive participants are ineligible because these participants are at increased risk of lethal infections when treated with marrow-suppressive therapy.

Sponsors & Collaborators

• Dana-Farber Cancer Institute: lead
• AstraZeneca: collaborator

Study Sites (1)

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Interventions

Cisplatin; adavosertib

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds

Results Point of Contact

• Title: Sara Tolaney, MD, MPH
• Organization: Dana-Farber Cancer Institute

Sara_Tolaney@dfci.harvard.edu

(877) 442-3324

Study Officials

• Sara Tolaney, MD, MPH

  Dana-Farber Cancer Institute

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: December 19, 2016
• First Posted: January 6, 2017
• Study Start: January 18, 2017
• Primary Completion: May 7, 2019
• Study Completion: November 30, 2020
• Last Updated: November 23, 2021
• Results First Posted: November 23, 2021

Record last verified: 2021-10

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)