Clinical Trials /

Trastuzumab Deruxtecan for the Treatment of HER2+ Newly Diagnosed or Recurrent Osteosarcoma

NCT04616560

Description:

This phase II trial studies the effects of trastuzumab deruxtecan in treating patients with HER2 positive osteosarcoma that is newly diagnosed or has come back (recurrent). Trastuzumab deruxtecan is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them.

Related Conditions:
  • Osteosarcoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Trastuzumab Deruxtecan for the Treatment of HER2+ Newly Diagnosed or Recurrent Osteosarcoma
  • Official Title: A Phase 2 Study of DS-8201a (NSC# 807708) in Adolescents, or Young Adults With Recurrent HER2+ Osteosarcoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2020-08428
  • SECONDARY ID: NCI-2020-08428
  • SECONDARY ID: PEPN1924
  • SECONDARY ID: PEPN1924
  • NCT ID: NCT04616560

Conditions

  • Osteosarcoma
  • Recurrent Osteosarcoma

Interventions

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

Purpose

This phase II trial studies the effects of trastuzumab deruxtecan in treating patients with HER2 positive osteosarcoma that is newly diagnosed or has come back (recurrent). Trastuzumab deruxtecan is a monoclonal antibody, called trastuzumab, linked to a chemotherapy drug called deruxtecan. Trastuzumab attaches to HER2 positive cancer cells in a targeted way and delivers deruxtecan to kill them.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To estimate the proportion of patients with recurrent measurable osteosarcoma treated with
      trastuzumab deruxtecan (DS-8201a) who are event free (%EF) at 24 weeks.

      SECONDARY OBJECTIVES:

      I. To assess the safety of DS-8201a in patients with recurrent osteosarcoma. II. To describe
      the pharmacokinetics of DS-8201a in patients with recurrent osteosarcoma.

      III. To estimate the objective response rate (ORR), event free survival (EFS) and overall
      survival (OS) of patients with recurrent, measurable osteosarcoma.

      EXPLORATORY OBJECTIVES:

      I. To describe the relationship between potential biomarkers and response to DS-8201a.

      II. To evaluate quantitative circulating tumor deoxyribonucleic acid (DNA) (ctDNA) and
      circulating tumor cells (CTCs) as a surrogate markers of response in recurrent osteosarcoma.

      OUTLINE:

      Patients receive trastuzumab deruxtecan intravenously (IV) over 30-90 minutes on day 1.
      Treatment repeats every 21 days for 35 cycles in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up at 6 months.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (trastuzumab deruxtecan)ExperimentalPatients receive trastuzumab deruxtecan IV over 30-90 minutes on day 1. Treatment repeats every 21 days for 35 cycles in the absence of disease progression or unacceptable toxicity.
  • Trastuzumab Deruxtecan

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have had histologic verification of osteosarcoma at original diagnosis
             or relapse

               -  Patients with diagnoses of osteosarcoma and confirmed HER2 expression of > 10% of
                  osteosarcoma cells are eligible for the intervention

                    -  Note: There is a mandatory tissue submission for HER2 staining during the
                       Step 0 Eligibility Screening process. Metastatic tissue, when possible from
                       the most recent relapse, is strongly preferred for HER2 staining over
                       archival tissue from primary resection or diagnostic biopsy. The evaluation
                       period for HER2 staining to determine eligibility for therapy will be less
                       than 4 weeks from screening enrollment

          -  Patients must have measurable disease according to Response Evaluation Criteria in
             Solid Tumors (RECIST) 1.1. Patients with clinically inactive brain metastases may be
             included in the study. Patients with treated brain metastases that are no longer
             symptomatic and who require no treatment with corticosteroids or anticonvulsants may
             be included in the study if they have recovered from the acute toxic effect of
             radiotherapy

          -  Patient's current disease state must be one for which they have received at least
             standard initial therapy, defined as systemic therapy combined with either radiation
             or surgery for local control of the primary tumor at diagnosis. Prior therapy after
             relapse is not required

          -  Patients must have a performance status corresponding to Eastern Cooperative Oncology
             Group (ECOG) scores of 0 or 1. Use Karnofsky for patients > 16 years of age and Lansky
             for patients =< 16 years of age. Patients who are non-ambulatory as a result of prior
             surgical treatment for osteosarcoma should be considered ambulatory for the purposes
             of assessing performance status

          -  Patients must have recovered from the acute toxic effects of all prior anti-cancer
             therapy and must meet the following minimum duration from prior anti-cancer directed
             therapy prior to enrollment. If after the required timeframe, the numerical
             eligibility criteria are met, e.g., blood count criteria, the patient is considered to
             have recovered adequately

               -  Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive:
                  For agents not listed, the duration of this interval must be discussed with the
                  study chair and the study-assigned Research Coordinator prior to enrollment

                    -  >= 21 days after the last dose of myelosuppressive chemotherapy (42 days if
                       prior nitrosourea)

               -  Anti-cancer agents not known to be myelosuppressive (e.g., not associated with
                  reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the
                  last dose of agent

               -  Antibodies: >= 4 weeks (28 days) must have elapsed from infusion of last dose of
                  antibody, and toxicity related to prior antibody therapy must be recovered to
                  grade =< 1

               -  Corticosteroids

               -  Hematopoietic growth factors: >= 14 days after the last dose of a long-acting
                  growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor. For
                  agents that have known adverse events occurring beyond 7 days after
                  administration, this period must be extended beyond the time during which adverse
                  events are known to occur

               -  Interleukins, interferons and cytokines (other than hematopoietic growth
                  factors): >= 21 days after the completion of interleukins, interferon or
                  cytokines (other than hematopoietic growth factors)

               -  Stem cell Infusions (with or without total body irradiation [TBI]):

                    -  Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem
                       cell infusion including donor lymphocyte infusion (DLI) or boost infusion:
                       >= 84 days after infusion and no evidence of graft versus host disease
                       (GVHD)

                    -  Autologous stem cell infusion including boost infusion: >= 30 days

               -  Vellular therapy: >= 30 days after the completion of any type of cellular therapy
                  (e.g., modified T cells, natural killer [NK] cells, dendritic cells, etc.)

               -  Radiation therapy (XRT)/external beam irradiation including protons: >= 4 weeks
                  (28 days) including palliative radiation therapy to the chest. >= 14 days after
                  palliative local XRT to areas other than the chest or for whole brain
                  radiotherapy

               -  Radiopharmaceutical therapy (e.g., radiolabeled antibody, samarium): >= 42 days
                  after systemically administered radiopharmaceutical therapy

               -  Patients must not have received prior HER2 therapies including antibody drug
                  conjugates (e.g. TDM-1 or DS-8201a), HER2 directed cellular therapies, HER2
                  receptor therapy (e.g. trastuzumab, pertuzumab) or small molecule antagonists of
                  HER2 (e.g lapatinib or neratinib)

          -  Patients must be at least 7 days from the date of last surgery

          -  Peripheral absolute neutrophil count (ANC) >= 1000/mm^3, (granulocyte
             colony-stimulating factor [G-CSF] administration is not allowed within 1 week prior to
             Step 1 screening assessment) (for patients with solid tumors without known bone marrow
             involvement)

          -  Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving
             platelet transfusions for at least 7 days prior to enrollment) (for patients with
             solid tumors without known bone marrow involvement)

          -  Hemoglobin >= 8.0 g/dL at baseline (Red Blood Cell transfusion is not allowed within 1
             week prior to screening assessment) (for patients with solid tumors without known bone
             marrow involvement)

          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 60
             mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows:

               -  Age: 12 to < 13 years; Maximum serum creatinine (mg/dL): 1.2 (male); 1.2 (female)

               -  Age: 13 to < 16 years; Maximum serum creatinine (mg/dL): 1.5 (male); 1.4 (female)

               -  Age: >= 16 years; Maximum serum creatinine (mg/dL): 1.7 (male); 1.4 (female)

                    -  For participants less than 18 years of age that screen fail only based on
                       creatinine, a 24 hour urine collection may be used instead to confirm
                       eligibility. A calculated GFR > 60 mL/min/1.73 m^2 using a 24 hour
                       collection will meet criteria for inclusion on this trial

          -  Bilirubin (sum of conjugated + unconjugated or total) =< 1.5 x upper limit of normal
             (ULN) for age. For patients with documented Gilbert's syndrome (unconjugated
             hyperbilirubinemia) bilirubin must be < 3 x ULN for age (patients with solid tumors)

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) and
             serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) =< 3
             x ULN. (if liver metastases present =< 5 x ULN). For the purpose of this study, the
             ULN for ALT is 45 U/L regardless of baseline and the ULN for AST is 50 U/L regardless
             of baseline (patients with solid tumors)

          -  Serum albumin >= 2.5 g/dL (patients with solid tumors)

          -  International normalized ratio (INR)/prothrombin time (PT) and either partial
             thromboplastin or activated partial thromboplastin time (aPTT) =< 1.5 x ULN (patients
             with solid tumors)

          -  Shortening fraction of >= 27% by echocardiogram, or ejection fraction of >= 50% by
             either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days
             before Step 1 enrollment

          -  Corrected QT interval (QTc) prolongation to < 470 ms (females) or < 450 ms (males)
             based on average triplicate 12-lead electrocardiogram (ECG)

          -  Pulse oximetry > 93% on room air

          -  Patients with seizure disorder may be enrolled if on anticonvulsants and well
             controlled as evidenced by no increase in seizure frequency in the prior 7 days

          -  Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE]
             version [v]5) resulting from prior chemotherapy, surgery, and/or radiation must be =<
             grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is
             eligible

          -  All patients and/or their parents or legally authorized representatives must sign a
             written informed consent. Assent, when appropriate, will be obtained according to
             institutional guidelines

        Exclusion Criteria:

          -  Pregnant, planning to become pregnant, or breast-feeding women will not be entered on
             this study because there is yet no available information regarding human fetal or
             teratogenic toxicities. Pregnancy tests must be obtained in girls who are
             post-menarchal. Males or females of reproductive potential may not participate unless
             they have agreed to use two effective methods of birth control, including a medically
             accepted barrier or contraceptive method (e.g., male or female condom) for the
             duration of the study and upon completion of the study and for at least 7 months for
             females and 4 months for males after the last dose of study drug. Abstinence is an
             acceptable method of birth control

               -  Methods considered as highly effective methods of contraception include:

                    -  Combined (estrogen and progestogen containing) hormonal contraception
                       associated with inhibition of ovulation:

                         -  Oral

                         -  Intravaginal

                         -  Transdermal

                    -  Progestogen-only hormonal contraception associated with inhibition of
                       ovulation:

                         -  Oral

                         -  Injectable

                         -  Implantable

                    -  Intrauterine device (IUD)

                    -  Intrauterine hormone-releasing system (IUS)

                    -  Bilateral tubal occlusion

                    -  Vasectomized partner

                    -  Complete sexual abstinence defined as refraining from heterosexual
                       intercourse. Periodic abstinence (calendar, symptothermal, post-ovulation
                       methods) is not an acceptable method of contraception

          -  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). 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 enrolment 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

          -  Patients receiving corticosteroids who have not been on a stable or decreasing dose of
             corticosteroid for at least 7 days prior to enrollment are not eligible. If used to
             modify immune adverse events related to prior therapy, >= 14 days must have elapsed
             since last dose of corticosteroid

          -  Patients who are currently receiving another investigational drug are not eligible

          -  Patients who are currently receiving other anti-cancer agents are not eligible

          -  Patients who are receiving cyclosporine, tacrolimus or other agents to prevent
             graft-versus-host disease post bone marrow transplant are not eligible for this trial

          -  Patients who are receiving chloroquine or hydroxychloroquine within 14 days are not
             eligible for this trial

          -  Patients who have received a prior solid organ transplantation are not eligible

          -  Patients with a medical history of myocardial infarction within 180 days before
             enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association
             Class II to IV) or troponin levels consistent with myocardial infarction as defined
             according to the manufacturer 28 days prior to enrollment are not eligible

          -  Patients who have a pleural effusion, ascites or pericardial effusion that requires
             drainage, peritoneal shunt, or Cell-free and Concentrated Ascites Reinfusion Therapy
             (CART) are not eligible

          -  Patients who have 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 are not eligible

          -  Patients with a known history of severe hypersensitivity to DS-8201a or any excipient
             contained in the DS-8201a drug formulation are not eligible

          -  Patients who have an uncontrolled infection or non-healing surgical site are not
             eligible

          -  Patients with a known history of substance abuse or any other clinically significant
             medical conditions (i.e. psychological conditions) that may, in the opinion of the
             investigator, interfere with the patient's participation in the clinical study or
             evaluation of the clinical study results are not eligible

          -  Patients who have pulmonary compromise, ex hypoxia, 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.), or prior pneumonectomy are not eligible

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

          -  Patients who have a pleural effusion, ascites or pericardial effusion that requires
             drainage, peritoneal shunt, or cell-free and concentrated ascites reinfusion therapy
             (CART) are not eligible. (Drainage and CART are not allowed within 2 weeks prior to
             screening assessment)

          -  Patients who, in the opinion of the investigator, may not be able to comply with the
             safety monitoring requirements of the study are not eligible
      
Maximum Eligible Age:39 Years
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Percent of patient event free
Time Frame:At 24 weeks
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to 6 months
Safety Issue:
Description:Toxicity tables will be constructed to summarize the observed incidence by type of toxicity and grade. A patient will be counted only once for a given toxicity for the highest grade of that toxicity reported for that patient. Toxicity information recorded will include the type, severity, time of onset, time of resolution, and the probable association with the study regimen.
Measure:Time to progression
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Progression free survival
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Overall survival
Time Frame:Up to 1 year
Safety Issue:
Description:
Measure:Event free survival
Time Frame:From study enrollment until the first occurrence of an event, defined as a relapse, disease progression, or death from any cause, assessed up to 1 year
Safety Issue:
Description:
Measure:Response rates
Time Frame:Up to 1 year
Safety Issue:
Description:Will be calculated as the percent of evaluable patients who are responders, and confidence intervals will be constructed accounting for the two-stage design. The percent of responders will be estimated with 95% confidence intervals.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

February 21, 2021