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A Dose Escalation and Expansion Study of TRX518 in Combination With Cyclophosphamide Plus Avelumab in Advanced Solid Tumors

NCT03861403

Description:

This is a Phase 1b/2a dose escalation and expansion, multi-center study to be conducted in 2 phases: - Phase 1b - Dose Escalation Part 1 (Doublet Therapy) - Dose Escalation Part 2 (Triplet Therapy) - Phase 2a - Dose Expansion (Triplet Therapy) Approximately 125 adult patients with histologically confirmed advanced solid tumors requiring therapy will be enrolled in the study. It is expected that approximately 24 patients will be enrolled in up to 4 cohorts, 2 cohorts in Dose Escalation Part 1 and 2 cohorts in Dose Escalation Part 2, of up to 6 patients per cohort. Up to 98 additional patients will be enrolled in the Dose Expansion phase of the study to achieve 88 evaluable patients (i.e., received at least 1 dose of study drug(s) and have 1 evaluable post-baseline modified RECIST v1.1 tumor response assessment; for mCRPC, assessment of soft tissue response will be per modified RECIST v1.1 and bone progression assessment will be per PCWG3 guidelines or discontinued treatment due to death, toxicity, or clinical progression) over 4 independent expansion groups.In either phase (1b or 2a), patients discontinuing for reasons unrelated to study treatment toxicity prior to completion of Cycle (C) 1 may be replaced to achieve the number of required evaluable patients per cancer type following consultation with the Sponsor. Data from each cohort in the Dose Escalation phase will be evaluated independently for safety and dose limiting toxicities (DLTs) prior to dose escalation and again prior to the Dose Expansion phase.

Related Conditions:
  • Breast Carcinoma
  • Fallopian Tube Carcinoma
  • Malignant Solid Tumor
  • Ovarian Carcinoma
  • Primary Peritoneal Carcinoma
  • Prostate Adenocarcinoma
  • Prostate Undifferentiated Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: A Dose Escalation and Expansion Study of TRX518 in Combination With Cyclophosphamide Plus Avelumab in Advanced Solid Tumors
  • Official Title: A Dose Escalation and Expansion Study of TRX518 in Combination With Cyclophosphamide Plus Avelumab in Advanced Solid Tumors

Clinical Trial IDs

  • ORG STUDY ID: TRX518-004
  • NCT ID: NCT03861403

Conditions

  • Solid Tumors
  • Advanced Triple Negative Breast Cancer
  • Advanced Hormone Receptor Positive/Endocrine Refractory Breast Cancer
  • Advanced Metastatic Castration-Resistant Prostate Cancer
  • Advanced Platinum-Resistant Ovarian Cancer

Interventions

DrugSynonymsArms
TRX518Advanced Hormone Receptor+/Endocrine Refractory Breast Cancer
CyclophosphamideAdvanced Hormone Receptor+/Endocrine Refractory Breast Cancer
AvelumabBAVENCIO®Advanced Hormone Receptor+/Endocrine Refractory Breast Cancer

Purpose

This is a Phase 1b/2a dose escalation and expansion, multi-center study to be conducted in 2 phases: - Phase 1b - Dose Escalation Part 1 (Doublet Therapy) - Dose Escalation Part 2 (Triplet Therapy) - Phase 2a - Dose Expansion (Triplet Therapy) Approximately 125 adult patients with histologically confirmed advanced solid tumors requiring therapy will be enrolled in the study. It is expected that approximately 24 patients will be enrolled in up to 4 cohorts, 2 cohorts in Dose Escalation Part 1 and 2 cohorts in Dose Escalation Part 2, of up to 6 patients per cohort. Up to 98 additional patients will be enrolled in the Dose Expansion phase of the study to achieve 88 evaluable patients (i.e., received at least 1 dose of study drug(s) and have 1 evaluable post-baseline modified RECIST v1.1 tumor response assessment; for mCRPC, assessment of soft tissue response will be per modified RECIST v1.1 and bone progression assessment will be per PCWG3 guidelines or discontinued treatment due to death, toxicity, or clinical progression) over 4 independent expansion groups.In either phase (1b or 2a), patients discontinuing for reasons unrelated to study treatment toxicity prior to completion of Cycle (C) 1 may be replaced to achieve the number of required evaluable patients per cancer type following consultation with the Sponsor. Data from each cohort in the Dose Escalation phase will be evaluated independently for safety and dose limiting toxicities (DLTs) prior to dose escalation and again prior to the Dose Expansion phase.

Trial Arms

NameTypeDescriptionInterventions
All Solid TumorsExperimentalPhase 1b, Part 1 Dose Escalation: TRX518 + CTX Combination (28-Day Cycle): Subjects receive the following treatment: Fixed dose of TRX518 administered intravenously on D2 and D16 per cycle Assigned dose of cyclophosphamide administered intravenously on C1D1 and may be re-administered on D1 of a subsequent cycle Phase 1b, Part 2 Dose Escalation: TRX518 + CTX + avelumab in (28-Day Cycle): Subjects receive the following treatment: Fixed dose of TRX518 administered intravenously on D2 and D16 per cycle Fixed dose of avelumab administered intravenously on D2 and D16 per cycle Fixed dose of cyclophosphamide administered at the MTD from Part 1 intravenously on C1D1 and may be re-administered on D1 of a subsequent cycle
  • TRX518
  • Cyclophosphamide
  • Avelumab
Advanced Triple Negative Breast CancerExperimentalPhase 2a Dose Expansion: TRX518 + CTX Combination + avelumab (28-Day Cycle): Subjects receive the following treatment: Fixed dose of TRX518 administered intravenously on D2 and D16 per cycle Fixed dose of avelumab administered intravenously on D2 and D16 per cycle Fixed dose of cyclophosphamide identified in Phase 1b administered on C1D1 and may be re-administered on D1 of a subsequent cycle
  • TRX518
  • Cyclophosphamide
  • Avelumab
Advanced Hormone Receptor+/Endocrine Refractory Breast CancerExperimentalPhase 2a Dose Expansion: TRX518 + CTX Combination + avelumab (28-Day Cycle): Subjects receive the following treatment: Fixed dose of TRX518 administered intravenously on D2 and D16 per cycle Fixed dose of avelumab administered intravenously on D2 and D16 per cycle Fixed dose of cyclophosphamide identified in Phase 1b administered on C1D1 and may be re-administered on D1 of a subsequent cycle
  • TRX518
  • Cyclophosphamide
  • Avelumab
Advanced Metastatic Castration-Resistant Prostate CancerExperimentalPhase 2a Dose Expansion: TRX518 + CTX Combination + avelumab (28-Day Cycle): Subjects receive the following treatment: Fixed dose of TRX518 administered intravenously on D2 and D16 per cycle Fixed dose of avelumab administered intravenously on D2 and D16 per cycle Fixed dose of cyclophosphamide identified in Phase 1b administered on C1D1 and may be re-administered on D1 of a subsequent cycle
  • TRX518
  • Cyclophosphamide
  • Avelumab
Advanced Platinum-Resistant Ovarian CancerExperimentalPhase 2a Dose Expansion: TRX518 + CTX Combination + avelumab (28-Day Cycle): Subjects receive the following treatment: Fixed dose of TRX518 administered intravenously on D2 and D16 per cycle Fixed dose of avelumab administered intravenously on D2 and D16 per cycle Fixed dose of cyclophosphamide identified in Phase 1b administered on C1D1 and may be re-administered on D1 of a subsequent cycle
  • TRX518
  • Cyclophosphamide
  • Avelumab

Eligibility Criteria

        Inclusion Criteria:

          -  Advanced Solid Malignancies in Dose Escalation Parts 1 and 2:

               -  Histologically documented metastatic or locally advanced, incurable solid
                  malignancy.

               -  At least one prior line of systemic therapy for metastatic or locally advanced
                  disease.

          -  Advanced Triple Negative Breast Cancer (Dose Expansion):

               -  Histologically proven invasive breast carcinoma with triple-negative receptor
                  status.

               -  At least 1 but no more than 2 prior lines of chemotherapy for metastatic or
                  locally advanced disease.

          -  Advanced Hormone Receptor-Positive/Endocrine-Refractory Breast Cancer (Dose
             Expansion):

               -  Histologically proven invasive breast carcinoma with hormone receptor+, HER2-
                  status.

               -  Only postmenopausal women are eligible. - Previously received at least 1 line of
                  aromatase inhibitor ± cyclin dependent kinase 4 and 6 (CDK4/6) inhibitor therapy.
                  Prior combination therapies of AI or selective estrogen receptor degrader (SERD
                  [fulvestrant]) ± CDK 4/6 inhibitor or AI plus everolimus will be permitted. Up to
                  1 prior line of systemic chemotherapy for metastatic disease is allowed.

          -  Advanced Metastatic Castration-Resistant Prostate Cancer (Dose Expansion):

               -  Histologically or cytologically confirmed prostate adenocarcinoma or poorly
                  differentiated carcinoma of the prostate.

               -  Surgically or medically castrated, with testosterone levels of < 50 ng/dL (< 2.0
                  nM). If a patient is being treated with LHRH agonists, this therapy must have
                  been initiated at least 4 weeks prior to treatment start and must be continued
                  throughout the study.

               -  Patients must have received ≥1 androgen receptor (AR) signaling inhibitors and
                  had disease progression RECIST v1.1 after no more than 1 prior chemotherapy for
                  mCRPC.

          -  Advanced Platinum-Resistant Ovarian Cancer (Dose Expansion):

               -  Histologically or cytologically confirmed diagnosis of metastatic, advanced, or
                  recurrent platinum-resistant epithelial ovarian, primary peritoneal or fallopian
                  tube cancer.

               -  Platinum-resistant ovarian cancer defined as disease progression following a
                  response within 180 days following the last administered dose of platinum
                  therapy. Patients who have lack of response (SD) or disease progression while
                  receiving the most recent platinum-based therapy are not eligible.

               -  Received up to 3 lines of systemic therapy for platinum-sensitive disease, with
                  the most recent regimen platinum-containing, and no prior systemic therapy for
                  platinum-resistant or refractory disease.

          -  General:

               -  Tumor tissue for mandatory pre-treatment and on-treatment biopsies.

               -  One or more tumors measurable on radiographic imaging defined by RECIST 1.1.

               -  Adult patients ≥18 years of age.

               -  ECOG performance status (PS) score of 0 or 1.

               -  Life expectancy of at least 12 weeks.

               -  Disease-free of active second/secondary or prior malignancies for ≥2 years, with
                  the exception of currently treated basal cell or squamous cell carcinoma of the
                  skin or carcinoma in-situ of the cervix or breast.

               -  Acceptable liver, renal, hematologic and coagulation function.

        Exclusion Criteria:

          -  Hematologic malignancies or multiple myeloma.

          -  For the Dose Expansion cohorts the following cancers are not permitted:

               -  Any of the following pure histologies of ovarian cancer: germ cell, sex cord
                  stroma, carcinosarcoma, or sarcoma.

               -  Small cell or pure neuroendocrine prostate carcinoma that has not yet been
                  treated with at least one line of platinum-based chemotherapy (prostate
                  adenocarcinoma with immunohistochemical neuroendocrine differentiation but
                  without histological small cell that is naïve to platinum-based chemotherapy will
                  be allowed.)

               -  Inflammatory breast cancer.

          -  New York Heart Association Class III or IV cardiac disease, myocardial infarction
             within the past 6 months, or unstable arrhythmia.

          -  Cardiac function:

               -  Known ejection fraction of <50% by gated radionuclide study (e.g., multi-gated
                  acquisition scan);

               -  Fridericia-corrected QT interval (QTcF) >470 msec (female) or >450 msec (male),
                  or history of congenital long QT syndrome;

               -  Any ECG abnormality, including pericarditis, that in the Investigator's opinion,
                  would preclude safe participation in the study.

          -  Active, uncontrolled bacterial, viral, or fungal infections within 7 days of study
             entry requiring systemic therapy.

          -  Active autoimmune disease that has required systemic treatment in the past 2 years.
             Replacement therapy (thyroxine, insulin, or physiologic corticosteroid replacement
             therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of
             systemic treatment.

          -  Known clinically important respiratory impairment.

               -  History of (non-infectious) pneumonitis that required steroids or current
                  pneumonitis.

               -  History of interstitial lung disease.

          -  Clinically significant gastrointestinal disorders, such as perforation,
             gastrointestinal bleeding, or diverticulitis.

          -  Known to be human immunodeficiency virus (HIV) positive or have hepatitis B surface
             antigen (HBSAg) or hepatitis C antibodies (HCAb) unless hepatitis C virus (HCV) RNA is
             undetected/negative.

          -  History of major organ transplant (i.e., heart, lungs, liver, and kidney).

          -  History of an allogeneic bone marrow transplant.

          -  History of an autologous bone marrow transplant within 90 days of study entry.

          -  Symptomatic central nervous system (CNS) malignancy or metastasis. Patients with
             treated CNS metastases are eligible, provided their disease is radiographically
             stable, asymptomatic, and they are not currently receiving corticosteroids and/or
             anticonvulsants. Radiation must have been completed at least 14 days prior to study
             entry. Screening of asymptomatic patients without a history of CNS metastases is not
             required.

          -  Serious nonmalignant disease that could compromise protocol objectives in the opinion
             of the Investigator and/or the Sponsor.

          -  Pregnant or nursing women.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1b: Number of subjects with dose limiting toxicities which will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE v5.0)
Time Frame:Baseline through 30 days post last dose (5 months)
Safety Issue:
Description:To determine the objective response rate according to modified RECIST v1.1

Secondary Outcome Measures

Measure:To determine the objective disease control rate (ODCR) according to modified RECIST 1.1 in breast and ovarian cancer groups
Time Frame:Baseline to study completion (approximately 4 months)
Safety Issue:
Description:
Measure:To determine the objective disease control rate (ODCR) according to modified RECIST 1.1 and PCWG3 guidelines in prostate cancer group
Time Frame:Baseline to study completion (approximately 4 months)
Safety Issue:
Description:
Measure:To determine the duration of response according to modified RECIST 1.1 in breast and ovarian cancer groups
Time Frame:Baseline to study completion (approximately 4 months)
Safety Issue:
Description:
Measure:To determine the duration of response according to modified RECIST 1.1 and PCWG criteria in prostate cancer group
Time Frame:Baseline to study completion (approximately 4 months)
Safety Issue:
Description:
Measure:To determine the progression free survival according to RECIST 1.1 in breast and ovarian cancer groups
Time Frame:Baseline to study completion (approximately 4 months)
Safety Issue:
Description:
Measure:To determine the progression free survival according to RECIST 1.1 and PCWG3 criteria in prostate cancer group
Time Frame:Baseline to study completion (approximately 4 months)
Safety Issue:
Description:
Measure:To determine overall survival (OS) in all cancer groups
Time Frame:Baseline to study completion (approximately 4 months)
Safety Issue:
Description:
Measure:To determine the PSA response in prostate cancer group
Time Frame:Baseline to study completion (approximately 4 months)
Safety Issue:
Description:
Measure:Evaluate the effect of TRX518 in combination with cyclophosphamide and avelumab on lymphoid cell subset numbers and function
Time Frame:Various timepoints through study completion (approximately 4 months)
Safety Issue:
Description:
Measure:Time to peak concentration (Tmax)
Time Frame:Various timepoints through study completion (approximately 4 months)
Safety Issue:
Description:Observations of the distribution, duration of effects and chemical changes of TRX518 and avelumab in the body and the effects and routes of the body's elimination of TRX518 and avelumab
Measure:TRX518 and avelumab peak concentration (Cmax)
Time Frame:Various timepoints through study completion (approximately 4 months)
Safety Issue:
Description:Observations of the distribution, duration of effects and chemical changes of TRX518 and avelumab in the body and the effects and routes of the body's elimination of TRX518 and avelumab
Measure:Area under the curve (AUC)
Time Frame:Various timepoints through study completion (approximately 4 months)
Safety Issue:
Description:Observations of the distribution, duration of effects and chemical changes of TRX518 and avelumab in the body and the effects and routes of the body's elimination of TRX518 and avelumab
Measure:Assess TRX518 and avelumab immunogenicity
Time Frame:Various timepoints through study completion (approximately 4 months)
Safety Issue:
Description:

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Active, not recruiting
Lead Sponsor:Leap Therapeutics, Inc.

Trial Keywords

  • Metastatic
  • Stage III or IV
  • Recurrent
  • Refractory
  • Solid tumors
  • Breast cancer
  • Prostate cancer
  • Ovarian cancer

Last Updated

November 13, 2019