Clinical Trials /

Testing the Biological Effects of DS-8201a on Patients With Advanced Cancer

NCT04294628

Description:

This phase I trial studies the biological effects of DS-8201a on patients with HER2 positive cancer that has spread to other places in the body (advanced). DS-8201a works by binding to a protein called HER2 that is present on the surface of tumor cells. This allows DS-8201a to kill the tumor cells by damaging their deoxyribonucleic acid (DNA), resulting in tumor cell death. This study looks at how DS-8201a may affect the levels of certain proteins and immune cells in tumors and how well the drug works against tumor cells by examining cells from a small piece tumor taken before and after DS-8201a is given.

Related Conditions:
  • Malignant Solid Tumor
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Testing the Biological Effects of DS-8201a on Patients With Advanced Cancer
  • Official Title: Pilot Study of DS-8201a Pharmacodynamics in Patients With HER2-Expressing Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-01206
  • SECONDARY ID: NCI-2020-01206
  • SECONDARY ID: 10346
  • SECONDARY ID: 10346
  • NCT ID: NCT04294628

Conditions

  • Metastatic Malignant Neoplasm
  • Refractory Malignant Neoplasm
  • Unresectable Malignant Neoplasm

Interventions

DrugSynonymsArms
Trastuzumab DeruxtecanDS-8201, DS-8201a, Enhertu, Fam-trastuzumab Deruxtecan-nxki, WHO 10516Treatment (trastuzumab deruxtecan)

Purpose

This phase I trial studies the biological effects of DS-8201a on patients with HER2 positive cancer that has spread to other places in the body (advanced). DS-8201a works by binding to a protein called HER2 that is present on the surface of tumor cells. This allows DS-8201a to kill the tumor cells by damaging their deoxyribonucleic acid (DNA), resulting in tumor cell death. This study looks at how DS-8201a may affect the levels of certain proteins and immune cells in tumors and how well the drug works against tumor cells by examining cells from a small piece tumor taken before and after DS-8201a is given.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To assess the effects of trastuzumab deruxtecan (DS-8201a) on topoisomerase 1 cleavable
      complex (Top1cc) formation in biopsy specimens from patients with HER2-expressing advanced
      solid tumors, at early and late post-treatment time points, thereby establishing the degree
      and duration of DS-8201 target engagement.

      SECONDARY OBJECTIVES:

      I. To assess any associations between plasma concentrations of DS-8201a and the effects of
      DS-8201a on Top1cc formation in tumor biopsy specimens.

      II. To determine the safety and tolerability of DS-8201a administered intravenously every 3
      weeks, in 21-day cycles, at a dose of 5.4 mg/kg.

      III. To determine the overall response rate (complete response [CR] + partial response [PR])
      for patients administered intravenously with DS-8201a every 3 weeks, in 21-day cycles, at a
      dose of 5.4 mg/kg.

      EXPLORATORY OBJECTIVES:

      I. To evaluate the effects of DS-8201a on CD8+ T cell infiltration and activation in tumor,
      tumor PD-L1 and HER2 expression, and DDR signaling (gamma H2AX, RAD51, and phosphorylated
      [p]NBS1) in biopsy specimens.

      II. To examine genomic alterations in circulating tumor DNA (ctDNA) that may be associated
      with DS-8201a response or resistance.

      III. To examine any associations between baseline tumor HER2 amplification or HER2 expression
      level and response to DS-8201a.

      IV. To evaluate the effects of DS-8201a on tumor levels of HER2 and DDR-associated proteins.

      V. To examine any tumor genomic alterations that may be associated with resistance to
      DS-8201a.

      OUTLINE:

      Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1.
      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)ExperimentalPatients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
  • Trastuzumab Deruxtecan

Eligibility Criteria

        Inclusion Criteria:

          -  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

          -  Patients must have measurable or evaluable disease

          -  Patients must have HER2-positive or HER2-expressing tumors as defined by Clinical
             Laboratory Improvement Act (CLIA)-certified labs. Patients must have either:

               -  A tumor HER2 immunohistochemistry (IHC) score of 1+ or greater (as determined by
                  a CLIA-certified IHC test, per criteria specified) or

               -  A tumor with HER2 amplification (as determined by CLIA-certified in situ
                  hybridization (ISH) or a CLIA-certified next-generation sequencing assay)

          -  Patients with HER2 mutations are eligible

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

          -  Absolute neutrophil count >= 1,500/mcL (within 8 days of enrollment)

          -  Platelets >= 100,000/mcL (within 8 days of enrollment)

          -  Leukocytes >= 3,000/mcL (within 8 days of enrollment)

          -  Hemoglobin >= 9 g/dL (>= 8.0 g/dL for gastric cancer [GC] only) (within 8 days of
             enrollment)

          -  Serum albumin >= 2.5 g/dL (GC only) (within 8 days of enrollment)

          -  Total bilirubin =< 1.5 x institutional upper limit of normal (=< 3 x upper limit of
             normal in the presence of documented Gilbert's syndrome or liver metastases at
             baseline) (within 8 days of enrollment)

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 3 x institutional upper limit of normal OR =< 5 x institutional upper limit of
             normal for patients with liver metastases at baseline (within 8 days of enrollment)

          -  Creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance >= 60
             mL/min/1.73 m^2 for patients with creatinine levels above 1.5 x institutional normal
             (within 8 days of enrollment)

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

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

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

          -  Willingness to provide blood samples for research purposes

          -  Patients must have a lesion or lesions amenable to biopsy and must be willing to
             undergo 3 core needle biopsy procedures for research purposes

          -  Patients must have left ventricular ejection fraction (LVEF) >= 50% by either an
             echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days prior to
             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 a CD4 count of greater than 250 cells/mcL over the past 6 months
                  on this same anti-retroviral regimen and must not have had a CD4 count < 200
                  cells/ul over the past 2 years, unless it was deemed related to the cancer and/or
                  immunotherapy-induced bone marrow suppression

                    -  For patients who have received chemotherapy in the past 6 months, a CD4
                       count < 250 cells/ul during chemotherapy is permitted as long as viral loads
                       were undetectable during this same chemotherapy

               -  They must have an undetectable viral load and a CD4 count >= 250 cells/uL within
                  8 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 treated brain metastases are eligible if follow-up brain imaging after
             central nervous system (CNS)-directed therapy shows no evidence of progression for >=
             1 month after treatment of the brain metastases

          -  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

          -  The effects of DS-8201a on the developing human fetus are unknown. For this reason and
             because HER2 antibodies conjugated to topoisomerase 1 inhibitor agents are known to be
             teratogenic, women of child-bearing potential and men must agree to use adequate
             contraception (hormonal or barrier method of birth control or abstinence) prior to
             study entry and for the duration of study participation and for at least 4.5 months
             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 4.5 months after completion of DS-8201a 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

          -  Subjects must not freeze, donate, or retrieve for their own use ova or sperm starting
             at screening, throughout the study period, and for at least 4.5 months after the final
             study drug administration. Preservation of sperm or ova should be considered prior to
             enrollment in this study

          -  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

        Exclusion Criteria:

          -  Patients who have had chemotherapy (including antibody drug therapy, retinoid therapy,
             hormonal therapy for cancer) within 4 weeks or five half-lives, whichever is shorter,
             for small-molecule targeted agents such as 5-fluorouracil-based agents, folinate
             agents, weekly paclitaxel; 6 weeks for nitrosoureas or mitomycin C

          -  Patients with any of the following pulmonary-related illnesses:

               -  A history of (non-infectious) interstitial lung disease (ILD) that required
                  steroids, current ILD, or for whom suspected ILD cannot be ruled out by imaging
                  at screening

               -  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

          -  Patients who have had radiation therapy within 4 weeks (2 weeks for palliative
             stereotactic radiation therapy)

          -  Patients who have had immunotherapy, including monoclonal antibody therapy, within 4
             weeks

          -  Patients who have had a major surgery within 4 weeks

          -  Patients who have had radiotherapy to the chest within 4 weeks or non-abdominal
             palliative stereotactic radiation therapy within 2 weeks

          -  Patients who are receiving any other investigational agents

          -  History of allergic reactions attributed to compounds of similar chemical or biologic
             composition to DS-8201a (e.g., other topoisomerase I inhibitors) or the inactive
             ingredients in the drug product

          -  Patients who have a history of severe hypersensitivity reactions to other monoclonal
             antibodies

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

          -  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 spinal cord compression or clinically active central nervous system
             metastases, defined as untreated and symptomatic, or requiring therapy with
             corticosteroids or anticonvulsants to control associated symptoms

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

          -  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 (e.g., grade 2 chemotherapy-induced neuropathy) may be
             eligible per the discretion of the investigator after consultation with the sponsor
             medical monitor or designee. Subjects should no longer be symptomatic nor require
             treatment with corticosteroids or anticonvulsants and must have recovered from the
             acute toxic effect of radiotherapy

          -  Patients with substance abuse or any other medical conditions that would increase the
             safety risk to the subject or interfere with participation of the subject or
             evaluation of the clinical study in the opinion of the investigator

          -  Patients with uncontrolled intercurrent illness

          -  Patients with psychiatric illness/social situations that would limit compliance with
             study requirements
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Early topoisomerase 1 cleavable complex (Top1cc)/deoxyribonucleic acid (DNA) damage response (DDR)
Time Frame:Up to day 1 of cycle 3 (each cycle is 21 days) or optionally, up to time of disease progression or restaging follow-up
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Association between plasma concentrations of DS-8201a and Top1cc formation
Time Frame:Up to day 1 of cycle 3 (each cycle is 21 days) or optionally, up to time of disease progression or restaging follow-up
Safety Issue:
Description:The association between plasma concentrations of DS-8201a and Top1cc formation will be assessed by computing the sample correlation between the area under the DS-8201a plasma concentration curve (AUC) and the initial change in Top1cc (from baseline to cycle 1 day 7 [C1D7]). Will also compute the sample correlation between the maximum plasma concentration of DS-8201a and the initial change in Top1cc (from baseline to C1D7). These relationships will also be summarized graphically using scatterplots and overlaid LOWESS curves.
Measure:Incidence of adverse events
Time Frame:Up to 30 days post-treatment
Safety Issue:
Description:Descriptive analyses of Common Terminology Criteria for Adverse Events data will be performed.
Measure:Overall response rate
Time Frame:From the start of the treatment until disease progression/recurrence
Safety Issue:
Description:Will estimate the overall response rate (complete response + partial response) among eligible patients who have received at least one dose of DS-8201a. A 95% confidence interval for this response rate will also be computed. For this analysis, response classifications will follow Response Evaluation Criteria in Solid Tumors version 1.1 guidelines.

Details

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

Last Updated

March 3, 2020