Clinical Trials /

Testing the Combination of DS-8201a and Olaparib in HER2-Expressing Cancers With Expansion in Patients With Endometrial Cancer

NCT04585958

Description:

This phase I trial identifies the side effects and best dose of DS-8201a and olaparib in treating patients with HER2-expressing cancers that have spread to other places in the body or cannot be removed by surgery or endometrial cancer. Olaparib is a drug that blocks an enzyme involved in many cell functions, including the repair of deoxyribonucleic acid (DNA) damage. Blocking this enzyme may help keep tumor cells from repairing their damaged DNA, causing them to die. DS-8201a is an antibody-drug conjugate. This agent has two components: an antibody component and a chemotherapy component. The antibody component is attached to the chemotherapy molecules. Upon administration of DS-8201a, the antibody targets and binds to tumor cells that have abundant HER2 (human-epidermal growth factor receptor 2), which is a protein on the surface of some tumor cells. The chemotherapy then enters the cells and blocks DNA replication in the tumor cells with abundant HER2, causing them to die. Giving DS-8201a and olaparib may shrink or stabilize the cancer.

Related Conditions:
  • Endometrial Serous Adenocarcinoma
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Combination of DS-8201a and Olaparib in HER2-Expressing Cancers With Expansion in Patients With Endometrial Cancer
  • Official Title: A Phase I Study of DS-8201a in Combination With Olaparib in HER2-Expressing Malignancies

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-07841
  • SECONDARY ID: NCI-2020-07841
  • SECONDARY ID: 10355
  • SECONDARY ID: 10355
  • SECONDARY ID: UM1CA186709
  • NCT ID: NCT04585958

Conditions

  • Endometrial Serous Adenocarcinoma
  • Metastatic Malignant Solid Neoplasm
  • Unresectable Malignant Solid Neoplasm

Interventions

DrugSynonymsArms
OlaparibAZD 2281, AZD-2281, AZD2281, KU-0059436, Lynparza, PARP Inhibitor AZD2281Treatment (trastuzumab deruxtecan, olaparib)
Trastuzumab DeruxtecanDS-8201, DS-8201a, Enhertu, Fam-trastuzumab Deruxtecan-nxki, WHO 10516Treatment (trastuzumab deruxtecan, olaparib)

Purpose

This phase I trial identifies the side effects and best dose of DS-8201a and olaparib in treating patients with HER2-expressing cancers that have spread to other places in the body or cannot be removed by surgery or endometrial cancer. Olaparib is a drug that blocks an enzyme involved in many cell functions, including the repair of deoxyribonucleic acid (DNA) damage. Blocking this enzyme may help keep tumor cells from repairing their damaged DNA, causing them to die. DS-8201a is an antibody-drug conjugate. This agent has two components: an antibody component and a chemotherapy component. The antibody component is attached to the chemotherapy molecules. Upon administration of DS-8201a, the antibody targets and binds to tumor cells that have abundant HER2 (human-epidermal growth factor receptor 2), which is a protein on the surface of some tumor cells. The chemotherapy then enters the cells and blocks DNA replication in the tumor cells with abundant HER2, causing them to die. Giving DS-8201a and olaparib may shrink or stabilize the cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability of the combination of trastuzumab deruxtecan
      (DS-8201a) in combination with olaparib, and to determine the recommended phase 2 dose
      (RP2D).

      II. To evaluate the safety and tolerability of this combination in a dose expansion cohort in
      patients with uterine serous carcinoma.

      SECONDARY OBJECTIVES:

      I. To observe and record anti-tumor activity as measured by objective response rate (ORR),
      clinical benefit rate, progression-free survival (PFS), and duration of response (DoR).

      II. To measure baseline HER2 expression by immunohistochemistry (IHC) in a central laboratory
      and correlate with response in the dose escalation and in the dose expansion.

      III. To evaluate the plasma pharmacokinetic (PK) profiles of olaparib and DS-8201a
      metabolites when administered in combination in the dose escalation and in the dose
      expansion.

      IV. To determine markers of DNA damage response (DDR) in tumor specimens at baseline and
      on-treatment in patients with uterine serous carcinoma in the dose expansion.

      EXPLORATORY OBJECTIVES:

      I. To measure baseline HER2 expression by immune-mass spectroscopy, and correlate with
      baseline central IHC and with response in the dose escalation and in the dose expansion.

      II. To measure the formation of topoisomerase I cleaved complex formation (TOP1cc) in blood
      specimens and correlate with response in the dose escalation and in the dose expansion.

      III. To measure the formation of TOP1cc in tumor specimens at baseline and on-treatment and
      correlate with response in patients with uterine serous carcinoma in the dose expansion.

      IV. To measure changes in HER2 expression over the course of treatment by IHC and immune
      multiple reaction monitoring-mass spectrometry (immunoMRM) and correlate with response in
      patients with uterine serous carcinoma in the dose expansion.

      V. To determine biomarkers of response and resistance in tumor specimens and blood specimens,
      including whole exome sequencing (WES) and ribonucleic acid (RNA) sequencing.

      OUTLINE: This is a dose-escalation study.

      Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1 and
      olaparib orally (PO) twice daily (BID) on days 1-21. Cycles repeat every 21 days in the
      absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up for 30 days.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (trastuzumab deruxtecan, olaparib)ExperimentalPatients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1 and olaparib PO BID on days 1-21. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Olaparib
  • Trastuzumab Deruxtecan

Eligibility Criteria

        Inclusion Criteria:

          -  DOSE ESCALATION PHASE

          -  Patients must have histologically confirmed malignancy that is metastatic or
             unresectable and for which standard curative or palliative measures do not exist or
             are no longer effective

          -  DOSE EXPANSION PHASE

          -  Patients must have histologically confirmed uterine serous carcinoma with at least one
             lesion suitable for biopsy without significant risk to the patient

          -  Patient disease must be evaluable or measurable by Response Evaluation Criteria in
             Solid Tumors (RECIST) version 1.1

          -  DOSE ESCALATION AND DOSE EXPANSION PHASES

          -  Patients must have had at least one prior line of cytotoxic chemotherapy

          -  Patients can have received an unlimited number of additional lines of chemotherapy,
             targeted therapy, biologic therapy, or hormonal therapy

          -  Patients must have HER2-positive or HER2-expressing tumors determined by a Clinical
             Laboratory Improvement Act (CLIA)-certified laboratory. Specific requirement of HER2
             status is outlined below:

               -  HER2 1-3+ expression by IHC OR

               -  HER2 amplification by next generation sequencing panel (NGS) or in situ
                  hybridization (ISH) OR

               -  If local testing is not feasible, patients will submit archival tissue for
                  central HER2 testing to determine eligibility. Patients with unknown or negative
                  HER2 testing will not be eligible

          -  Patients must have archival formalin-fixed paraffin-embedded (FFPE) tissue available
             for central confirmation of HER2 testing

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 1 (Karnofsky >= 70%)

          -  Hemoglobin >= 10.0 g/dL (within 14 days of randomization/enrollment)

          -  Absolute neutrophil count >= 1,000/mcL (within 14 days of randomization/enrollment)

               -  No administration of granulocyte colony-stimulating factor (G-CSF) is allowed
                  within 1 week prior to screening assessment

          -  Platelets >= 100,000/mcL (within 14 days of randomization/enrollment)

               -  No transfusions with red blood cells or platelets are allowed within 1 week prior
                  to screening assessment

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (ULN), (< 3 x ULN in the
             presence of documented Gilbert's syndrome or liver metastases at baseline) (within 14
             days of randomization/enrollment)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3 x institutional ULN (within 14 days of randomization/enrollment)

          -  International normalized ratio (INR) =< 1.5 x ULN/prothrombin time (PT) and activated
             partial thromboplastin time (aPTT) (within 14 days of randomization/enrollment)

          -  Creatinine =< 1.5 x institutional ULN (within 14 days of randomization/enrollment) OR

          -  Glomerular filtration rate (GFR) >= 51 mL/min/1.73 m^2 unless data exists supporting
             safe use at lower kidney function values, no lower than 30 mL/min/1.73 m^2 (using the
             Cockcroft-Gault Equation) (within 14 days of randomization/enrollment)

          -  Patients must have left ventricular ejection fraction (LVEF) >= 50% by either an
             echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before
             randomization/enrollment

          -  Patients who are human immunodeficiency virus (HIV) positive may participate IF they
             meet the following eligibility requirements:

               -  They must be stable on their anti-retroviral regimen, and they must be healthy
                  from an HIV perspective

               -  They must have an undetectable viral load and a CD4 count >= 250 cells/uL within
                  7 days of enrollment

               -  They must not be currently receiving prophylactic therapy for an opportunistic
                  infection and must not have had an opportunistic infection within the past 6
                  months

               -  HIV-infected patients should be monitored every 12 weeks for viral load and CD4
                  counts

          -  For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral
             load must be undetectable on suppressive therapy, if indicated

          -  Patients with a history of hepatitis C virus (HCV) infection must have been treated
             and cured. For patients with HCV infection who are currently on treatment, they are
             eligible if they have an undetectable HCV viral load

          -  Patients with brain metastases should be stable and off steroids and at least 4 weeks
             from radiation at the time of registration

          -  Patients with a prior or concurrent malignancy whose natural history or treatment does
             not have the potential to interfere with the safety or efficacy assessment of the
             investigational regimen are eligible for this trial

          -  Patients with known history or current symptoms of cardiac disease, or history of
             treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac
             function using the New York Heart Association Functional Classification. To be
             eligible for this trial, patients should be better than class 2B

          -  The effects of DS-8201a and olaparib on the developing human fetus are unknown. For
             this reason and because HER2 antibody conjugated to a topoisomerase 1 inhibitor agents
             as well as PARP inhibitors are known to be teratogenic; thus, women of child-bearing
             potential and men must agree to use highly effective contraception (hormonal or
             barrier method of birth control; abstinence) prior to study entry, for the duration of
             study participation, and for at least 7 months (women of childbearing potential
             [WOCBP] only) after the last dose of study drug. 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 DS-8201a and
             olaparib administration.

          -  Women of non-child-bearing potential defined as pre-menopausal females with a
             documented tubal ligation or hysterectomy; or postmenopausal defined as 12 months of
             spontaneous amenorrhea (in questionable cases, a blood sample with simultaneous
             follicle-stimulating hormone [FSH] > 40 mIU/mL and estradiol < 40 pg/mL [< 147 pmol/L]
             is confirmatory) are eligible. Females on hormone replacement therapy (HRT) and whose
             menopausal status is in doubt will be required to use one of the contraception methods
             outlined for women of child-bearing potential if they wish to continue their HRT
             during the study. Otherwise, they must discontinue HRT to allow confirmation of
             post-menopausal status prior to study enrollment. For most forms of HRT, at least 2-4
             weeks will elapse between the cessation of therapy and the blood draw; this interval
             depends on the type and dosage of HRT. Following confirmation of their post-menopausal
             status, they can resume use of HRT during the study without use of a contraceptive
             method

          -  Male subjects must not freeze or donate sperm starting at screening and throughout the
             study period, and at least 4 months after the final study drug administration.
             Preservation of sperm should be considered prior to enrollment in this study

          -  Female subjects must not donate, or retrieve for their own use, ova from the time of
             screening and throughout the study treatment period, and for at least 7 months after
             the final study drug administration

          -  Ability to understand and the willingness to sign a written informed consent document.
             Participants with impaired decision-making capacity (IDMC) who have a
             legally-authorized representative (LAR) and/or family member available will also be
             eligible

        Exclusion Criteria:

          -  Patients who have had chemotherapy (including antibody drug therapy) within 4 weeks
             with the following exceptions: 1 week for weekly paclitaxel; 2 weeks or five
             half-lives, whichever is longer, for small-molecule targeted agents such as
             5-fluorouracil-based agents, folinate agents, hormonal agents; or 6 weeks for
             nitrosoureas or mitomycin C

          -  Patients who have had radiation therapy within 4 weeks

          -  Patients who have had a major surgery within 4 weeks

          -  Patients who are receiving any other investigational agents

          -  For the dose expansion cohort: Patients who have received prior PARP inhibitors

          -  Patients with a history of (non-infectious) interstitial lung disease
             (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where
             suspected ILD/pneumonitis cannot be ruled out by imaging at screening

          -  Patients with clinically severe pulmonary compromise resulting from intercurrent
             pulmonary illnesses including, but not limited to, any underlying pulmonary disorder
             (i.e. pulmonary emboli within three months of the study enrollment, severe asthma,
             severe chronic obstructive pulmonary disease [COPD], restrictive lung disease, pleural
             effusion, etc.), and any autoimmune, connective tissue or inflammatory disorders with
             potential pulmonary involvement (i.e. rheumatoid arthritis, Sjogren's, sarcoidosis,
             etc.), or prior pneumonectomy

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to DS-8201a, the inactive ingredients in the drug product, olaparib, or
             severe hypersensitivity to other monoclonal antibodies

          -  Patients receiving any medications or substances that are moderate or strong
             inhibitors or inducers of CYP3A are ineligible. Because the lists of these agents are
             constantly changing, it is important to regularly consult a frequently-updated medical
             reference. 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

          -  Patients with a medical history of myocardial infarction within 6 months before
             randomization/enrollment, symptomatic congestive heart failure (CHF) (New York Heart
             Association class IIb to IV), troponin levels consistent with myocardial infarction as
             defined according to the manufacturer 28 days prior to randomization

          -  Patients with a corrected QT interval (QTc) prolongation to > 470 ms (females) or >
             450 ms (males) based on average of the screening triplicate 12-lead electrocardiogram
             (ECG)

          -  Patients with clinically significant corneal disease in the opinion of the
             investigator

          -  Patients with multiple primary malignancies within 3 years, except adequately resected
             non-melanoma skin cancer, curatively treated in-situ disease, and other solid tumors
             curatively treated

          -  Patients with an uncontrolled infection requiring IV antibiotics, antivirals, or
             antifungals

          -  Patients receiving chloroquine or hydroxychloroquine will require a washout period of
             >= 14 days to be eligible for the study

          -  Patients with unresolved toxicities from previous anticancer therapy, defined as
             toxicities (other than alopecia) not yet resolved to grade =< 1 or baseline. Subjects
             with chronic grade 2 toxicities may be eligible per the discretion of the investigator
             after consultation with the sponsor medical monitor or designee (e.g., grade 2
             chemotherapy-induced neuropathy)

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Pregnant women are excluded from this study because DS-8201a is a HER2 antibody
             conjugated to a topoisomerase 1 inhibitor agent with the potential for teratogenic or
             abortifacient effects. Because there is an unknown but potential risk for adverse
             events in nursing infants secondary to treatment of the mother with DS-8201a,
             breastfeeding should be discontinued if the mother is treated with DS-8201a. These
             potential risks may also apply to other agents used in this study
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose/recommended phase 2 dose
Time Frame:Up to 42 days
Safety Issue:
Description:Will be measured by Common Terminology Criteria for Adverse Events CTCAE version (v) 5.0 and analyzed using descriptive statistics.

Secondary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:ORR will be evaluated by Response Evaluation Criteria in Solid Tumors (RESIST) 1.1 criteria to determine the best overall response for evaluable patients.
Measure:Clinical benefit rate (CBR)
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:CBR will be evaluated by RESIST 1.1 criteria to determine the best overall response for evaluable patients.
Measure:Duration of response (DOR)
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:DOR will be evaluated by RESIST 1.1 criteria to determine the best overall response for evaluable patients. DOR will be described using the method of Kaplan-Meier.
Measure:HER2 expression
Time Frame:At baseline
Safety Issue:
Description:HER2 expression on archival specimens will be analyzed using current American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) breast cancer and gastric cancer scoring methods. The levels of HER2 expression (0, 1+, 2+, or 3+) will be determined and the number and percentage of patients in each category will be reported. Chi-squared test and regression modeling may be used to investigate any possible relationship of HER2 biomarker levels with anti-tumor efficacy.
Measure:Plasma pharmacokinetic (PK) profiles
Time Frame:Up to 30 days post treatment
Safety Issue:
Description:PK will be analyzed using descriptive statistics. Analysis of variance and regression model may be used to investigate any possible relationship of PK biomarker levels with anti-tumor efficacy
Measure:Markers of deoxyribonucleic acid (DNA) damage response (DDR)
Time Frame:At baseline and on-treatment
Safety Issue:
Description:Markers of DDR will be measured by multiplex IF in tumor specimens at baseline and on-treatment in patients with uterine serous carcinoma in the dose expansion cohort and correlating these markers with response.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

October 13, 2020