CISPLATIN + AZD-1775 In Breast Cancer

Sponsor
Dana-Farber Cancer Institute (Other)
Overall Status
Completed
CT.gov ID
NCT03012477
Collaborator
AstraZeneca (Industry)
34
1
1
46.4
0.7

Study Details

Study Description

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

Condition or Disease Intervention/Treatment Phase
Phase 2

Detailed Description

This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. "Investigational" means that the intervention is being studied.

The FDA (the U.S. Food and Drug Administration) has not approved AZD1775 as a treatment for any type of cancer. Cisplatin is FDA approved for other cancers and has been shown to be an active treatment for breast cancer.

AZD1775 is a drug that is designed to block a protein called Wee-1 which may control the ability of certain cancer cells to grow or divide. Cisplatin works by damaging the DNA inside the cancer cells which prevents them from dividing. By combining AZD1775 and Cisplatin, cancer cells may potentially be more effectively killed.

In this research study, the investigators are looking to determine whether the combination of AZD1775 and cisplatin is an effective treatment for triple negative breast cancer that has spread to other parts of the body.

Study Design

Study Type:
Interventional
Actual Enrollment :
34 participants
Allocation:
N/A
Intervention Model:
Single Group Assignment
Masking:
None (Open Label)
Primary Purpose:
Treatment
Official Title:
A Phase II Study of Cisplatin + AZD1775 in Metastatic Triple-negative Breast Cancer and Evaluation of pCDC2 as a Biomarker of Target Response
Actual Study Start Date :
Jan 18, 2017
Actual Primary Completion Date :
May 7, 2019
Actual Study Completion Date :
Nov 30, 2020

Arms and Interventions

Arm Intervention/Treatment
Experimental: cisplatin + AZD1775

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
chemotherapy
Other Names:
  • Platinol
  • Drug: AZD1775
    Wee1 tyrosine kinase inhibitor

    Outcome Measures

    Primary Outcome Measures

    1. Objective Response Rate [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]

      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.

    Secondary Outcome Measures

    1. 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 ).]

      Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.

    2. 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]

    3. 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]

    4. 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]

    5. 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]

      Formalin-fixed, paraffin-embedded (FFPE) biopsy specimens will be subjected to immunohistochemical analyses using standard procedures.

    6. Correlation Between Next Generation Sequencing of Tumors and Participant Outcomes [ORR evaluated every 6 weeks from the time of their first treatment; PFS evaluated rom date of initiation of study treatment; Biopsies will occur 5-48 hours after cycle 1 and 5-8hrs after cycle 2. Follow up approximately 3 years and 11 months.]

      Correlation compute between ORR and PFS, based on all participants data.

    Eligibility Criteria

    Criteria

    Ages Eligible for Study:
    18 Years and Older
    Sexes Eligible for Study:
    All
    Accepts Healthy Volunteers:
    No
    Inclusion Criteria:
    • 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

    • Serum creatinine ≤1.5 mg/dL OR measured creatinine clearance (CrCl) ≥45 mL/min as calculated by the Cockcroft-Gault method OR 24-hour measured urine CrCl ≥45mL/min

    • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 times the upper limit of normal. For patients with documented liver metastases, AST/ALT ≤ 5.0 times the upper limit of normal.

    • Patients on bisphosphonates may continue receiving bisphosphonate therapy during study treatment.

    • Availability of a tissue block from initial breast cancer diagnosis and/or metastatic recurrence. If a tissue block is not available, 10-20 unstained slides may be provided as an alternative. If unstained slides will be provided, they should not be sent until specifically requested by the DFCI study coordinator. If archival tumor tissue is not available, a fresh biopsy may be performed.

    • In the first stage of the trial, at least 10 patients with biopsy-accessible disease must be willing to undergo paired research biopsies. These 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. The exact timing of the biopsy relative to receipt of study treatment should be accurately recorded.

    • Biopsies may be done with local anesthesia or intravenous conscious sedation, according to standard institutional guidelines.

    • Research biopsies requiring general anesthesia are not allowed on this protocol unless a biopsy is being obtained simultaneously for clinical reasons, in the judgment of the patients' treating physician.

    • Patients who undergo an attempted on-treatment research biopsy and in whom inadequate tissue is obtained are still eligible to continue protocol therapy. They will not be required to undergo a repeat biopsy attempt.

    • If dosing is delayed placing the biopsy outside of the allowable window, the biopsy should be rescheduled to be within the window. If not feasible, the biopsy should be obtained as close to within the window as possible.

    • Fine needle aspirates (FNA) is not allowed

    • Female subjects of childbearing potential must have a negative serum pregnancy test at screening.

    • The effects of AZD1775 on the developing human fetus are unknown. Women of child-bearing potential and men must agree to use enhanced methods of contraception. All women are considered to be of childbearing potential unless they fulfill one of the following criteria at screening:

    • Post-menopausal defined as age ≥50 and amenorrheic for at least 12 months OR Women age <50 if they have been amenorrheic for at least 12 months and have a serum follicle-stimulating hormone (FSH) and luteinizing hormone (LH) level in the postmenopausal range (per institutional standards).

    • If women have documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy, or bilateral tubal ligation, they are considered post-menopausal.

    • Appropriate contraception should be used from the time of screening, throughout the duration of study participation, and for four months after the last dose of AZD1775. Acceptable methods of contraception include abstinence, tubal ligation, intra-uterine devices, and vasectomised partner. All methods of contraception (with the exception of total abstinence) should be used in combination with the use of a condom by the male sexual partner for intercourse. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the participants treating physician should be informed immediately. Additionally, male patients should refrain from donating sperm from the start of dosing until 6 months after discontinuing AZD1775. If male patients wish to father children they should be advised to arrange for freezing of sperm samples prior to the start of study treatment.

    • Participant must be able to swallow pills.

    • Participant may not have a percutaneous endoscopic gastrostomy (PEG) tube or be receiving total parenteral nutrition (TPN).

    • Ability to understand and the willingness to sign a written informed consent document.

    Exclusion Criteria:
    • 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.

    • Participant with mean resting corrected QT interval (specifically QTc calculated using the Fridericia formula [QTcF]) > 450 msec for males and > 470 msec for females, from 3 electrocardiograms (ECGs) performed within 2-5 minutes apart at study entry, or congenital long QT syndrome.

    Contacts and Locations

    Locations

    Site City State Country Postal Code
    1 Dana-Farber Cancer Institute Boston Massachusetts United States 02215

    Sponsors and Collaborators

    • Dana-Farber Cancer Institute
    • AstraZeneca

    Investigators

    • Principal Investigator: Sara Tolaney, MD, MPH, Dana-Farber Cancer Institute

    Study Documents (Full-Text)

    More Information

    Publications

    None provided.
    Responsible Party:
    Sara Tolaney, Principal Investigator, Dana-Farber Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT03012477
    Other Study ID Numbers:
    • 16-264
    First Posted:
    Jan 6, 2017
    Last Update Posted:
    Nov 23, 2021
    Last Verified:
    Oct 1, 2021
    Individual Participant Data (IPD) Sharing Statement:
    No
    Plan to Share IPD:
    No
    Studies a U.S. FDA-regulated Drug Product:
    Yes
    Studies a U.S. FDA-regulated Device Product:
    No
    Keywords provided by Sara Tolaney, Principal Investigator, Dana-Farber Cancer Institute
    Additional relevant MeSH terms:

    Study Results

    Participant Flow

    Recruitment Details
    Pre-assignment Detail
    Arm/Group Title Cisplatin + AZD1775
    Arm/Group Description 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).
    Period Title: Overall Study
    STARTED 34
    COMPLETED 34
    NOT COMPLETED 0

    Baseline Characteristics

    Arm/Group Title Cisplatin + AZD1775
    Arm/Group Description 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).
    Overall Participants 34
    Age (Years) [Median (Full Range) ]
    Median (Full Range) [Years]
    56
    Sex: Female, Male (Count of Participants)
    Female
    34
    100%
    Male
    0
    0%
    Race/Ethnicity, Customized (Count of Participants)
    Asian
    2
    5.9%
    White
    30
    88.2%
    Other
    2
    5.9%
    Region of Enrollment (participants) [Number]
    United States
    34
    100%

    Outcome Measures

    1. Primary Outcome
    Title Objective Response Rate
    Description 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.
    Time Frame 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Cisplatin + AZD1775
    Arm/Group Description 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).
    Measure Participants 34
    Number (95% Confidence Interval) [percentage of participants]
    26
    76.5%
    2. Secondary Outcome
    Title Median Progression-free Survival (PFS)
    Description Progression-free survival based on the Kaplan-Meier method is defined as the duration of time from study entry to documented disease progression (PD) or death. Per RECIST 1.1 criteria: progressive disease (PD) is at least a 20% increase in the sum of longest diameter (LD) of target lesions taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. PD for the evaluation of non-target lesions is the appearance of one or more new lesions and/or unequivocal progression of non-target lesions.
    Time Frame 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 ).

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Cisplatin + AZD1775
    Arm/Group Description 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).
    Measure Participants 34
    Median (95% Confidence Interval) [Months]
    4.9
    3. Secondary Outcome
    Title Change in pCDC2 After Therapy With AZD1775 in Paired Biopsies
    Description
    Time Frame 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

    Outcome Measure Data

    Analysis Population Description
    paired biopsies were not collected because of tissue accessible safety, and lack of efficacy
    Arm/Group Title Cisplatin + AZD1775
    Arm/Group Description 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).
    Measure Participants 0
    4. Secondary Outcome
    Title Number of p53 Mutations
    Description
    Time Frame 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Cisplatin + AZD1775
    Arm/Group Description 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).
    Measure Participants 30
    Number [p53 mutations per 1000 person years]
    0
    5. Secondary Outcome
    Title Number of of BRCA1/2 Mutation
    Description
    Time Frame 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Cisplatin + AZD1775
    Arm/Group Description 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).
    Measure Participants 30
    Number [BRCA1/2 mutations per 1000 person years]
    0
    6. Secondary Outcome
    Title Number of Patients Have Changes in Markers for DNA Damage
    Description Formalin-fixed, paraffin-embedded (FFPE) biopsy specimens will be subjected to immunohistochemical analyses using standard procedures.
    Time Frame 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

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Cisplatin + AZD1775
    Arm/Group Description 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).
    Measure Participants 30
    Count of Participants [Participants]
    30
    88.2%
    7. Secondary Outcome
    Title Correlation Between Next Generation Sequencing of Tumors and Participant Outcomes
    Description Correlation compute between ORR and PFS, based on all participants data.
    Time Frame ORR evaluated every 6 weeks from the time of their first treatment; PFS evaluated rom date of initiation of study treatment; Biopsies will occur 5-48 hours after cycle 1 and 5-8hrs after cycle 2. Follow up approximately 3 years and 11 months.

    Outcome Measure Data

    Analysis Population Description
    [Not Specified]
    Arm/Group Title Cisplatin + AZD1775
    Arm/Group Description 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).
    Measure Participants 30
    Number [correlation]
    0

    Adverse Events

    Time Frame AE was evaluated at day 1 of each cycle until the end of treatment, through study completion, average about 1 year
    Adverse Event Reporting Description Serious AEs (SAE) were defined as events with treatment-attribution of possibly, probably or definitely and grade 3 or higher. All remaining AEs are classified as Other AEs (OAE) including grade 3 or higher events with treatment-attribution of unlikely and unrelated plus all grade 1 and 2 events. Maximum grade toxicity by type was then calculated within SAE and OAE datasets. No further data is available to specify classification of other beyond the general term.
    Arm/Group Title Cisplatin + AZD1775
    Arm/Group Description 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).
    All Cause Mortality
    Cisplatin + AZD1775
    Affected / at Risk (%) # Events
    Total 1/34 (2.9%)
    Serious Adverse Events
    Cisplatin + AZD1775
    Affected / at Risk (%) # Events
    Total 13/34 (38.2%)
    Blood and lymphatic system disorders
    Anemia 3/34 (8.8%)
    Gastrointestinal disorders
    Diarrhea 7/34 (20.6%)
    Nausea 2/34 (5.9%)
    Infections and infestations
    Sepsis 1/34 (2.9%)
    Urinary tract infection 1/34 (2.9%)
    Investigations
    Alkaline phosphatase increased 1/34 (2.9%)
    Neutrophil count decreased 2/34 (5.9%)
    Metabolism and nutrition disorders
    Dehydration 1/34 (2.9%)
    Nervous system disorders
    Headache 1/34 (2.9%)
    Vascular disorders
    Thromboembolic event 1/34 (2.9%)
    Other (Not Including Serious) Adverse Events
    Cisplatin + AZD1775
    Affected / at Risk (%) # Events
    Total 34/34 (100%)
    Blood and lymphatic system disorders
    Anemia 11/34 (32.4%)
    Cardiac disorders
    Cardiac arrest 1/34 (2.9%)
    Cardiac disorders - Other 1/34 (2.9%)
    Sinus tachycardia 1/34 (2.9%)
    Ear and labyrinth disorders
    Ear and labyrinth disorders - Other 1/34 (2.9%)
    Hearing impaired 1/34 (2.9%)
    Tinnitus 7/34 (20.6%)
    Endocrine disorders
    Endocrine disorders - Other 1/34 (2.9%)
    Hypothyroidism 1/34 (2.9%)
    Gastrointestinal disorders
    Abdominal pain 3/34 (8.8%)
    Constipation 14/34 (41.2%)
    Diarrhea 17/34 (50%)
    Dyspepsia 2/34 (5.9%)
    Flatulence 1/34 (2.9%)
    Gastrointestinal disorders - Other 3/34 (8.8%)
    Nausea 29/34 (85.3%)
    Stomach pain 1/34 (2.9%)
    Vomiting 25/34 (73.5%)
    General disorders
    Edema limbs 3/34 (8.8%)
    Fatigue 27/34 (79.4%)
    Flu like symptoms 1/34 (2.9%)
    Irritability 1/34 (2.9%)
    Localized edema 1/34 (2.9%)
    Non-cardiac chest pain 1/34 (2.9%)
    Pain 9/34 (26.5%)
    Immune system disorders
    Allergic reaction 1/34 (2.9%)
    Infections and infestations
    Urinary tract infection 5/34 (14.7%)
    Injury, poisoning and procedural complications
    Bruising 1/34 (2.9%)
    Investigations
    Alanine aminotransferase increased 1/34 (2.9%)
    Alkaline phosphatase increased 1/34 (2.9%)
    Aspartate aminotransferase increased 3/34 (8.8%)
    Cardiac troponin T increased 1/34 (2.9%)
    Creatinine increased 3/34 (8.8%)
    Investigations - Other 1/34 (2.9%)
    Neutrophil count decreased 12/34 (35.3%)
    Platelet count decreased 6/34 (17.6%)
    Weight gain 3/34 (8.8%)
    Weight loss 2/34 (5.9%)
    Metabolism and nutrition disorders
    Acidosis 1/34 (2.9%)
    Anorexia 10/34 (29.4%)
    Dehydration 4/34 (11.8%)
    Hypocalcemia 1/34 (2.9%)
    Hypomagnesemia 1/34 (2.9%)
    Hyponatremia 1/34 (2.9%)
    Musculoskeletal and connective tissue disorders
    Arthralgia 1/34 (2.9%)
    Back pain 4/34 (11.8%)
    Chest wall pain 2/34 (5.9%)
    Muscle weakness upper limb 1/34 (2.9%)
    Myalgia 2/34 (5.9%)
    Neck pain 2/34 (5.9%)
    Pain in extremity 1/34 (2.9%)
    Nervous system disorders
    Cognitive disturbance 1/34 (2.9%)
    Dizziness 3/34 (8.8%)
    Dysgeusia 8/34 (23.5%)
    Headache 8/34 (23.5%)
    Nervous system disorders - Other 1/34 (2.9%)
    Peripheral sensory neuropathy 8/34 (23.5%)
    Sinus pain 1/34 (2.9%)
    Syncope 1/34 (2.9%)
    Psychiatric disorders
    Anxiety 1/34 (2.9%)
    Confusion 2/34 (5.9%)
    Depression 1/34 (2.9%)
    Insomnia 5/34 (14.7%)
    Renal and urinary disorders
    Chronic kidney disease 1/34 (2.9%)
    Reproductive system and breast disorders
    Breast pain 1/34 (2.9%)
    Respiratory, thoracic and mediastinal disorders
    Cough 6/34 (17.6%)
    Dyspnea 7/34 (20.6%)
    Pleural effusion 1/34 (2.9%)
    Pneumonitis 1/34 (2.9%)
    Skin and subcutaneous tissue disorders
    Alopecia 2/34 (5.9%)
    Dry skin 2/34 (5.9%)
    Palmar-plantar erythrodysesthesia syndrome 1/34 (2.9%)
    Pruritus 2/34 (5.9%)
    Rash acneiform 2/34 (5.9%)
    Rash maculo-papular 1/34 (2.9%)
    Skin and subcutaneous tissue disorders - Other 2/34 (5.9%)
    Vascular disorders
    Hot flashes 3/34 (8.8%)
    Lymphedema 3/34 (8.8%)
    Thromboembolic event 2/34 (5.9%)

    Limitations/Caveats

    [Not Specified]

    More Information

    Certain Agreements

    All Principal Investigators ARE employed by the organization sponsoring the study.

    There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

    Results Point of Contact

    Name/Title Sara Tolaney, MD, MPH
    Organization Dana-Farber Cancer Institute
    Phone (877) 442-3324
    Email Sara_Tolaney@dfci.harvard.edu
    Responsible Party:
    Sara Tolaney, Principal Investigator, Dana-Farber Cancer Institute
    ClinicalTrials.gov Identifier:
    NCT03012477
    Other Study ID Numbers:
    • 16-264
    First Posted:
    Jan 6, 2017
    Last Update Posted:
    Nov 23, 2021
    Last Verified:
    Oct 1, 2021