Clinical Trial: NCT02306161 - My Cancer Genome

NCT02306161

Description:

This randomized phase III trial studies how well combination chemotherapy with or without ganitumab works in treating patients with newly diagnosed Ewing sarcoma that has spread to other parts of the body. Immunotherapy with monoclonal antibodies, such as ganitumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Drugs used in chemotherapy, such as vincristine sulfate, doxorubicin hydrochloride, cyclophosphamide, ifosfamide, and etoposide phosphate, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. It is not yet known whether combination chemotherapy is more effective with or without ganitumab in treating patients with newly diagnosed Ewing sarcoma.

Related Conditions:

Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor

Recruiting Status:

Active, not recruiting

Phase:

Phase 3

URL:

https://clinicaltrials.gov/show/NCT02306161

Trial Eligibility

Document

Title

Brief Title: Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma
Official Title: Randomized Phase 3 Trial Evaluating the Addition of the IGF-1R Monoclonal Antibody Ganitumab (AMG 479, NSC# 750008) to Multiagent Chemotherapy for Patients With Newly Diagnosed Metastatic Ewing Sarcoma

Clinical Trial IDs

ORG STUDY ID: NCI-2014-02380
SECONDARY ID: NCI-2014-02380
SECONDARY ID: AEWS1221
SECONDARY ID: s15-00442
SECONDARY ID: AEWS1221
SECONDARY ID: AEWS1221
SECONDARY ID: U10CA180886
SECONDARY ID: U10CA098543
NCT ID: NCT02306161

Conditions

Metastatic Ewing Sarcoma
Metastatic Malignant Neoplasm in the Bone
Metastatic Malignant Neoplasm in the Bone Marrow
Metastatic Malignant Neoplasm in the Lung
Metastatic Peripheral Primitive Neuroectodermal Tumor of Bone
Peripheral Primitive Neuroectodermal Tumor of Soft Tissues

Interventions

Drug	Synonyms	Arms
Cyclophosphamide	(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719	Regimen A (VDC/IE)
Doxorubicin	Adriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, Hydroxyldaunorubicin	Regimen A (VDC/IE)
Doxorubicin Hydrochloride	5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, Rubex	Regimen A (VDC/IE)
Etoposide	Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16	Regimen A (VDC/IE)
Etoposide Phosphate	Etopophos	Regimen A (VDC/IE)
Ganitumab	AMG 479, Anti-IGF-1R Human Monoclonal Antibody AMG-479	Regimen B (VDC/IE + ganitumab)
Ifosfamide	Asta Z 4942, Asta Z-4942, Cyfos, Holoxan, Holoxane, Ifex, IFO, IFO-Cell, Ifolem, Ifomida, Ifomide, Ifosfamidum, Ifoxan, IFX, Iphosphamid, Iphosphamide, Iso-Endoxan, Isoendoxan, Isophosphamide, Mitoxana, MJF 9325, MJF-9325, Naxamide, Seromida, Tronoxal, Z 4942, Z-4942	Regimen A (VDC/IE)
Vincristine	Leurocristine, VCR, Vincrystine	Regimen A (VDC/IE)
Vincristine Sulfate	Kyocristine, Leurocristine Sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfate	Regimen A (VDC/IE)

Purpose

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine if event-free survival (EFS) in patients with newly diagnosed metastatic
      Ewing sarcoma treated with multiagent chemotherapy is improved with the addition of ganitumab
      (AMG 479).

      SECONDARY OBJECTIVES:

      I. To describe the toxicity of the addition of ganitumab to multimodality therapy for
      patients with newly diagnosed metastatic Ewing sarcoma.

      II. To compare overall survival in patients with newly diagnosed metastatic Ewing sarcoma
      treated with multiagent chemotherapy with and without the addition of ganitumab.

      EXPLORATORY OBJECTIVES:

      I. To compare bone marrow response rates in patients with newly diagnosed metastatic Ewing
      sarcoma treated with multiagent chemotherapy with and without the addition of ganitumab.

      II. To describe the toxicity of 6 months of ganitumab monotherapy as maintenance therapy
      following multimodality therapy in patients with newly diagnosed metastatic Ewing sarcoma.

      III. To describe trough levels of ganitumab in a cohort of patients with Ewing sarcoma < 21
      years of age treated with 18 mg/kg.

      IV. To describe the feasibility of and local failure rates following hypofractionated
      stereotactic body radiotherapy (SBRT) directed at bone metastases in patients with newly
      diagnosed metastatic Ewing sarcoma.

      V. To determine if EFS, overall survival, bone marrow response rates, and toxicity differ
      based on serum markers of the insulin-like growth factor 1 (IGF-1) pathway in patients with
      newly diagnosed metastatic Ewing sarcoma treated with interval compressed chemotherapy with
      and without the addition of ganitumab.

      VI. To determine if EFS, overall survival, and bone marrow response rates differ based on
      protein, deoxyribose nucleic acid (DNA), and ribonucleic acid (RNA) marker in patients with
      newly diagnosed metastatic Ewing sarcoma treated with interval compressed chemotherapy with
      and without the addition of ganitumab.

      VII. To evaluate bone marrow micrometastatic disease and tumor cell surface IGF-1R expression
      at diagnosis and after 3 and 6 cycles of study therapy in patients with newly diagnosed
      metastatic Ewing sarcoma.

      VIII. To determine if the presence of germline polymorphisms in EGFR correlate with response
      to multiagent therapy with and without ganitumab.

      IX. To investigate the ability of fludeoxyglucose F 18-positron emission tomography (FDG-PET)
      to augment conventional response assessment of primary Ewing sarcoma tumors by magnetic
      resonance imaging (MRI).

      X. To explore FDG-PET response at the primary tumor as a prognostic marker and as a
      predictive biomarker of clinical activity of IGF-1R inhibition in patients with newly
      diagnosed metastatic Ewing sarcoma.

      XI. To collect data on institutional testing for Ewing sarcoma breakpoint region 1 (EWSR1)
      translocation status in patients enrolling on study.

      XII. To explore the capacity of plasma cell-free DNA analysis to detect tumor-specific
      genetic changes at initial diagnosis and after initiation of protocol therapy.

      XIII. To collect a population of bone marrow metastatic tumor cells by flow cytometry for
      genomic profiling.

      OUTLINE: Patients are randomized to 1 of 2 treatment regimens. (As of 3/20/2019, the study is
      closed to accrual and patients in Regimen B no longer receive ganitumab.)

      REGIMEN A (vincristine sulfate, doxorubicin hydrochloride and cyclophosphamide [VDC] and
      ifosfamide and etoposide phosphate [IE]):

      INDUCTION THERAPY: Patients receive vincristine sulfate intravenously (IV) over 1 minute on
      day 1, doxorubicin hydrochloride IV over 1-15 minutes on days 1 and 2, and cyclophosphamide
      IV over 30-60 minutes on day 1 of weeks 1, 5, and 9, and ifosfamide IV over 1 hour on days 1
      to 5 and etoposide phosphate IV over 1-2 hours on days 1 to 5 of weeks 3, 7, and 11.

      LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation
      therapy.

      CONSOLIDATION THERAPY: Patients receive vincristine sulfate IV over 1 minute on day 1 of
      weeks 1, 7, 9, and 13; doxorubicin hydrochloride IV over 1-15 minutes on days 1 and 2 of
      weeks 1 and 7, cyclophosphamide IV over 30-60 minutes on day 1 of weeks 1, 7, 9, and 13,
      ifosfamide IV over 1 hour on days 1 to 5 of weeks 3, 5, 11, and 15, and etoposide phosphate
      IV over 1-2 hours on days 1 to 5 of weeks 3, 5, 11, and 15.

      METASTATIC SITE IRRADIATION: Patients with lung metastases undergo definitive SBRT or
      external beam radiation therapy (EBRT) over 5 days.

      REGIMEN B (VDC/IE + ganitumab):

      INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab
      IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11.

      LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation
      therapy.

      CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A.

      METASTATIC SITE IRRADIATION: Patients with lung metastases undergo definitive SBRT or EBRT
      over 5 days.

      After completion of study treatment, patients are followed for 10 years.

Trial Arms

Name	Type	Description	Interventions
Regimen A (VDC/IE)	Experimental	See Design Details.	Cyclophosphamide Doxorubicin Doxorubicin Hydrochloride Etoposide Etoposide Phosphate Ifosfamide Vincristine Vincristine Sulfate
Regimen B (VDC/IE + ganitumab)	Experimental	INDUCTION THERAPY: Patients receive Induction therapy as in Regimen A and receive ganitumab IV over 30-60 minutes or 60-120 minutes on day 1 of weeks 1, 3, 5, 7, 9, and 11. LOCAL CONTROL THERAPY: Between weeks 13-18, patients undergo surgery and/or radiation therapy. CONSOLIDATION THERAPY: Patients receive Consolidation therapy as in Regimen A. METASTATIC SITE IRRADIATION: Patients with lung metastases undergo definitive SBRT or EBRT over 5 days.	Cyclophosphamide Doxorubicin Doxorubicin Hydrochloride Etoposide Etoposide Phosphate Ganitumab Ifosfamide Vincristine Vincristine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  Patients with histologic diagnosis (by institutional pathologist) of newly diagnosed
             Ewing sarcoma or peripheral primitive neuroectodermal tumor (PNET) arising from bone
             or soft tissue and with metastatic disease involving lung, bone, bone marrow, or other
             metastatic site

          -  For the purpose of this study metastatic disease is defined as one or more of the
             following:

               -  Lesions which are discontinuous from the primary tumor, are not regional lymph
                  nodes, and do not share a bone or body cavity with the primary tumor; skip
                  lesions in the same bone as the primary tumor do not constitute metastatic
                  disease; skip lesions in an adjacent bone are considered bone metastases; if
                  there is any doubt whether lesions are metastatic, a biopsy of those lesions
                  should be performed

               -  Contralateral pleural effusion and/or contralateral pleural nodules

               -  Distant lymph node involvement

               -  Patients with pulmonary nodules are considered to have metastatic disease if the
                  patient has:

                    -  Solitary nodule >= 0.5 cm or multiple nodules of >= 0.3 cm unless lesion is
                       biopsied and negative for tumor

                    -  Patients with solitary nodule < 0.5 cm or multiple nodules < 0.3 cm are not
                       considered to have lung metastasis unless biopsy documents tumor

               -  Bone marrow metastatic disease is based on morphologic evidence of Ewing sarcoma
                  based on hematoxylin and eosin (H&E) stains; in the absence of morphologic
                  evidence of marrow involvement on H&E, patients with bone marrow involvement
                  detected ONLY by flow cytometry, reverse-transcriptase (RT)-polymerase chain
                  reaction (PCR), fluorescence in situ hybridization (FISH), or
                  immunohistochemistry will NOT be considered to have clinical bone marrow
                  involvement for the purposes of this study

                    -  This study requires bilateral bone marrow biopsies at study entry; the
                       suggested approach for patients with large pelvic tumors in which a
                       posterior iliac crest bone marrow biopsy would track through the tumor is to
                       instead undergo 2 marrow biopsies on the contralateral side (either 2
                       posterior biopsies or one posterior and one anterior biopsy)

               -  Bone metastasis: This study utilizes whole body FDG-PET scans to screen patients
                  for bone metastases; areas suspicious for bone metastasis based on FDG-PET scans
                  require confirmatory anatomic imaging with either MRI or computed tomography (CT)
                  (whole body FDG-PET/CT or FDG-PET/magnetic resonance [MR] scan acceptable); whole
                  body technetium bone scans may be performed at the discretion of the investigator
                  and are not required; for patients without other sites of metastatic disease
                  whose sole metastatic site to qualify for study entry is a single area suspicious
                  for bone metastasis identified by FDG-PET, confirmatory biopsy or anatomic
                  imaging evidence of an associated soft tissue mass at that site is required for
                  study entry

          -  Patients must have adequate tumor tissue to meet the minimum requirement for
             submission

          -  Enrolling institutions are reminded that submission of pre-treatment serum, tumor
             tissue and whole blood is required

          -  Patients should only have had a biopsy of the primary tumor without an attempt at
             complete or partial resection; patients will still be eligible if excision was
             attempted or accomplished as long as adequate anatomic imaging (MRI for most primary
             tumor sites) was obtained prior to surgery

          -  Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70
             mL/min/1.73 m^2 or a serum creatinine based on age/gender as follows (performed within
             7 days prior to enrollment):

               -  Age < 6 months: Maximum serum creatinine (mg/dL): 0.4 for males and females

               -  Age 6 months to < 1 year: Maximum serum creatinine (mg/dL): 0.5 for males and
                  females

               -  Age 1 to < 2 years: Maximum serum creatinine (mg/dL): 0.6 for males and females

               -  Age 2 to < 6 years: Maximum serum creatinine (mg/dL): 0.8 for males and females

               -  Age 6 to < 10 years: Maximum serum creatinine (mg/dL): 1 for males and females

               -  Age 10 to < 13 years: Maximum serum creatinine (mg/dL): 1.2 for males and females

               -  Age 13 to < 16 years: Maximum serum creatinine (mg/dL): 1.5 for males and 1.4 for
                  females

               -  Age >= 16 years: Maximum serum creatinine (mg/dL): 1.7 for males and 1.4 for
                  females

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) for age (performed within 7 days
             prior to enrollment), and

          -  Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) < 3 x
             upper limit of normal (ULN) for age (performed within 7 days prior to enrollment)
             (except for patients with liver metastasis who may enroll if ALT < 5 times ULN for
             age)

          -  Shortening fraction of >= 27% or

          -  Ejection fraction of >= 50%

          -  Patients must have a normal blood sugar level for age to participate; if an initial
             random draw (ie. non-fasting) blood glucose value is out of range, it is acceptable to
             repeat this test as a fasting draw

          -  All patients and/or their parents or legal guardians must sign a written informed
             consent

          -  All institutional, Food and Drug Administration (FDA), and National Cancer Institute
             (NCI) requirements for human studies must be met

        Exclusion Criteria:

          -  Patients with regional node involvement as their only site of disease beyond the
             primary tumor will not be eligible

          -  Patients whose primary tumors arise in the intra-dural soft tissue (e.g. brain and
             spinal cord) are not eligible

          -  Patients who have received prior chemotherapy or radiation therapy are not eligible

          -  Female patients of childbearing potential are not eligible unless a negative pregnancy
             test result has been obtained; lactating females are not eligible unless they have
             agreed not to breastfeed their infants for the duration of protocol therapy; sexually
             active patients of reproductive potential are not eligible unless they have agreed to
             use an effective contraceptive method for the duration of protocol therapy

          -  Patients with known pre-existing diabetes mellitus will be excluded from study

          -  Patients receiving chronic pharmacologic doses of corticosteroids are not eligible;
             for the purposes of eligibility, chronic exposure is defined as anticipated exposure
             of > 3 weeks, including the sum of both pre-enrollment and anticipated post-enrollment
             dosing; patients on acute corticosteroid therapy (=< 3 weeks of total planned
             exposure) must still meet the normal blood glucose requirement; patients receiving
             chronic inhaled corticosteroids or chronic physiologic replacement doses of
             corticosteroids are eligible

Maximum Eligible Age:	50 Years
Minimum Eligible Age:	N/A
Eligible Gender:	All
Healthy Volunteers:	No

Primary Outcome Measures

Measure:	Time to adverse analytic event (event-free survival [EFS])
Time Frame:	From the time of randomization, assessed up to 10 years
Safety Issue:
Description:	Will be defined to be disease-related event, diagnosis of a second malignant neoplasm, or death. The two regimens will be compared using the relative risk regression model with strata representing those used for randomization. A log-partial-likelihood one-sided test of size 0.025 will be used to compare the two regimens. A parametric model that treats disease progressions identified at routine visits as interval censored observations with the left censoring time as the date of the last screening prior to the identification of the relapse and other relapse times as being known exactly will be fit.

Secondary Outcome Measures

Measure:	Overall Survival
Time Frame:	From enrollment to death regardless of cause or last patient contact, assessed up to 10 years
Safety Issue:
Description:

Measure:	Overall toxicity of the addition of ganitumab to vincristine sulfate, doxorubicin hydrochloride and cyclophosphamide (VDC)/ifosfamide and etoposide (IE)
Time Frame:	Up to 30 days after last dose of study drug
Safety Issue:
Description:	Will be defined using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. The 95% confidence interval for the toxicity-event rate for each phase noted above for patients enrolled on the comparator therapy will be constructed.

Measure:	Sinusoidal obstructive disease (SOS) associated with the addition of ganitumab to VDC/IE
Time Frame:	Up to 30 days after last dose of study drug
Safety Issue:
Description:	A phase where a patient experiences any SOS will be considered a phase with an SOS toxicity-event. The effect of possible correlations between analytic units that arises because some analytic units are contributed by the same individual will be explored. A random effects binomial model where a Normally distributed random effect with 0 mean and unknown variance chi-squared is contributed by each unit in a pair of analytic units that arise from the same individual will be explored.

Measure:	Risk of death
Time Frame:	Up to 10 years
Safety Issue:
Description:	The relative risk for death and the naive p-value associated with the null hypothesis H0: relative risk for death is 1 will be estimated using the stratified partial likelihood for the relative risk regression model accounting for the factors used to stratify randomization at the time full information is obtained for the EFS comparison.

Measure:	Bone marrow response rates
Time Frame:	Up to 10 years
Safety Issue:
Description:	Each bone marrow evaluable patient will be assessed for the presence or absence of bone marrow metastatic disease over the interval between enrollment and the time of first local control measure or the end of the Induction reporting period, whichever comes first. Only one evaluation of best response will be used to classify the patient as complete responder (no evidence of marrow disease) or incomplete responder (residual marrow disease or progression). An estimate of the proportion of patients who achieve complete bone marrow response and an associated 95% confidence interval provided.

Measure:	Tolerability of maintenance ganitumab
Time Frame:	Up to 10 years
Safety Issue:
Description:	At the time each study progress report is prepared, the toxicity-event rate will be calculated and the one-sided test of size 0.05 of the null hypothesis that the toxicity-event rate is 25% will be performed.

Measure:	Ganitumab pharmacokinetics (PK)
Time Frame:	Prior to the first dose of ganitumab, prior to the second dose of ganitumab on Induction day 15, prior to the third dose of ganitumab on Induction day 29, prior to the sixth dose of ganitumab on Induction day 71 (Induction)
Safety Issue:
Description:	Results of this PK testing will be reported descriptively, with an emphasis on the proportion of patients achieving a trough serum ganitumab concentration >= 10 ug/mL at a dose of 18 mg/kg IV every 3 weeks. Additional trough levels in Maintenance will allow for estimation of accumulation, half-life, and steady state clearance of ganitumab.

Measure:	Feasibility of stereotactic body radiotherapy (SBRT)
Time Frame:	Up to 10 years
Safety Issue:
Description:	Defined as an individual that has SBRT planned for at least one site, starts the treatment of metastatic disease phase of the protocol and has at least 85% of tumor sites planned to be treated with SBRT receive successful SBRT. Successful treatment delivery is defined as a treatment plan that is acceptable or has only minor variation as assessed by Imaging and Radiation Oncology Core Rhode Island (formerly Quality Assurance Review Center). In addition to this feasibility assessment, efficacy will be evaluated by comparing the failure rate at irradiated bone metastases with SBRT and external beam radiation therapy (EBRT), recognizing selection bias between patients treated with SBRT or EBRT.

Details

Phase:	Phase 3
Primary Purpose:	Interventional
Overall Status:	Active, not recruiting
Lead Sponsor:	National Cancer Institute (NCI)

Last Updated

April 15, 2021

Clinical Trials /

Combination Chemotherapy With or Without Ganitumab in Treating Patients With Newly Diagnosed Metastatic Ewing Sarcoma