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

NCT03861403 | Terminated Phase 1 FDA Drug

• 1 other identifier: TRX518-004
• Study Type: interventional
• Target: 10
• Locations: 1 country
• Sites: 4

Brief Summary

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.

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

Keywords

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

Outcome Measures

Primary Outcomes (4)

• 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)

  Baseline through 30 days post last dose (5 months)

• Phase 1b: Identify the recommended Phase 2 dose (RP2D) of CTX in combination with fixed doses of TRX518 ± avelumab

  Baseline through end of Cycle 1 (Day 28)

• Phase 2a: Efficacy in Breast and Ovarian Cancer Groups: objective response rate

  To determine the objective response rate according to modified RECIST v1.1

  Baseline to study completion (approximately 4 months)

• Phase 2a: Efficacy in Prostate Cancer Group: objective response rate

  To determine the objective response rate according to modified RECIST 1.1 and PCWG3 guidelines

  Baseline to study completion (approximately 4 months)

Secondary Outcomes (13)

• To determine the objective disease control rate (ODCR) according to modified RECIST 1.1 in breast and ovarian cancer groups

  Baseline to study completion (approximately 4 months)

• To determine the objective disease control rate (ODCR) according to modified RECIST 1.1 and PCWG3 guidelines in prostate cancer group

  Baseline to study completion (approximately 4 months)

• To determine the duration of response according to modified RECIST 1.1 in breast and ovarian cancer groups

  Baseline to study completion (approximately 4 months)

• To determine the duration of response according to modified RECIST 1.1 and PCWG criteria in prostate cancer group

  Baseline to study completion (approximately 4 months)

• To determine the progression free survival according to RECIST 1.1 in breast and ovarian cancer groups

  Baseline to study completion (approximately 4 months)

Study Arms (5)

All Solid Tumors

EXPERIMENTAL

Phase 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

Drug: TRX518; Drug: Cyclophosphamide; Drug: Avelumab

Advanced Triple Negative Breast Cancer

EXPERIMENTAL

Phase 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

Drug: TRX518; Drug: Cyclophosphamide; Drug: Avelumab

Advanced Hormone Receptor+/Endocrine Refractory Breast Cancer

EXPERIMENTAL

Phase 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

Drug: TRX518; Drug: Cyclophosphamide; Drug: Avelumab

Advanced Metastatic Castration-Resistant Prostate Cancer

EXPERIMENTAL

Phase 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

Drug: TRX518; Drug: Cyclophosphamide; Drug: Avelumab

Advanced Platinum-Resistant Ovarian Cancer

EXPERIMENTAL

Phase 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

Drug: TRX518; Drug: Cyclophosphamide; Drug: Avelumab

Interventions

TRX518 DRUG

Administered by IV infusion

Advanced Hormone Receptor+/Endocrine Refractory Breast Cancer; Advanced Metastatic Castration-Resistant Prostate Cancer; Advanced Platinum-Resistant Ovarian Cancer; Advanced Triple Negative Breast Cancer; All Solid Tumors

Cyclophosphamide DRUG

Administered by IV infusion

Advanced Hormone Receptor+/Endocrine Refractory Breast Cancer; Advanced Metastatic Castration-Resistant Prostate Cancer; Advanced Platinum-Resistant Ovarian Cancer; Advanced Triple Negative Breast Cancer; All Solid Tumors

Avelumab DRUG

Administered by IV infusion

Also known as: BAVENCIO®

Advanced Hormone Receptor+/Endocrine Refractory Breast Cancer; Advanced Metastatic Castration-Resistant Prostate Cancer; Advanced Platinum-Resistant Ovarian Cancer; Advanced Triple Negative Breast Cancer; All Solid Tumors

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Leap Therapeutics, Inc.: lead
• Pfizer: collaborator
• Merck KGaA, Darmstadt, Germany: collaborator

Study Sites (4)

Horizon Oncology Research

Lafayette, Indiana, 47905, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cleveland Clinic

Cleveland, Ohio, 44195, United States

Location

University of Virginia

Charlottesville, Virginia, 22903, United States

Location

MeSH Terms

Conditions

Neoplasm Metastasis; Recurrence; Breast Neoplasms; Prostatic Neoplasms; Ovarian Neoplasms

Interventions

Cyclophosphamide; avelumab

Condition Hierarchy (Ancestors)

Neoplastic Processes; Neoplasms; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Disease Attributes; Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Genital Diseases, Male; Genital Diseases; Urogenital Diseases; Prostatic Diseases; Male Urogenital Diseases; Endocrine Gland Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Genital Neoplasms, Female; Endocrine System Diseases; Gonadal Disorders

Intervention Hierarchy (Ancestors)

Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 26, 2019
• First Posted: March 4, 2019
• Study Start: May 20, 2019
• Primary Completion: July 14, 2020
• Study Completion: July 14, 2020
• Last Updated: November 30, 2023

Record last verified: 2023-11

Locations

US (4)