A Study of Metronomic CP and JX-594 in Patients With Advanced Breast Cancer and Advanced Soft-tissue Sarcoma (METROmaJX)

NCT02630368 | Unknown Phase 1 DMC

• 2 other identifiers: IB 2014-022014-001078-33
• Study Type: interventional
• Target: 197
• Locations: 1 country
• Sites: 1

Brief Summary

Assessment of the efficacy and safety of JX-594 and metronomic cyclophosphamide in patients with advanced soft-tissue sarcoma and advanced breast cancer, once the Maximum Tolerated Dose have been determined (phase I trial). Phase I study: this is a prospective open-labeled phase I trial based on a dose escalating study design assessing two dose levels of JX594 when prescribed in combination with metronomic cyclophosphamide. Phase II trials with two treatments strategies: Metronomic CP + JX-594: phase II study sarcoma: this is a monocentric, randomized two-arm non comparative phase 2 study assessing efficacy and safety of JX-594 in association with metronomic cyclophosphamide in patients with advanced soft-tissue sarcoma. Metronomic CP + JX-594: phase II study breast cancer: this is a monocentric, single-arm phase II study, assessing efficacy and safety of JX-594 in association with metronomic cyclophosphamide in patients with advanced breast cancer. Metronomic CP + JX-594 + Avelumab: phase II study sarcoma: this is a monocentric, single arm phase II study assessing efficacy and safety of avelumab in combination with IT JX-594 and metronomic cyclophosphamide in patients with advanced soft-tissue sarcoma. Metronomic CP + JX-594 + Avelumab:: phase II study breast cancer: this is a monocentric, single-arm phase II study, assessing efficacy and safety of avelumab in combination with IT JX-594 and metronomic cyclophosphamide in patients with advanced breast cancer.

Conditions

Solid Tumors; Soft-tissue Sarcoma; Breast Cancer

Keywords

Advanced Soft-tissue Sarcoma; Advanced Breast Cancer; Maximum Tolerated Dose; Efficacy and safety; Immunotherapy

Outcome Measures

Primary Outcomes (5)

• Phase Ib : Maximum Tolerated Dose evaluated on the first cycle (D1 to D28) of the combination of JX-594 And metronomic cyclophosphamide

  the MTD is defined as the highest dose at which no more than 1 in 6 of the patients in the cohort experienced a DLT in the first treatment cycle

  during the first cycle (28 days)

• Phase II : Advanced soft-tissue sarcoma: Assessment of the antitumor activity of the association of JX-594 and metronomic cyclophosphamide based on 6 month non-progression (CR, PR or SD more than 24 weeks) following RECIST v1.1 criteria

  Non-progression is defined as complete or partial response or stable disease, as per RECIST v1.1

  Phase II : 6 months after the beginning of treatment

• Phase II : Advanced Breast cancer: Assessment of the antitumor activity of the association of JX-594 and metronomic cyclophosphamide Efficacy will be defined based on objective response under treatment (CR or PR) following RECIST v1.1 criteria

  Objective response is defined as complete or partial response as per RECIST v1.1

  Phase II : 6 months after the beginning of treatment

• Phase II : Advanced soft-tissue sarcoma: Assessment of the antitumor activity of Avelumab in combination with IT JX-594 and metronomic cyclophosphamide based on 6 month non-progression (CR, PR or SD more than 24 weeks) following RECIST v1.1 criteria

  Non-progression is defined as complete or partial response or stable disease, as per RECIST v1.1

  Phase II : 6 months after the beginning of treatment

• Phase II : Advanced Breast cancer: Assessment of the antitumor activity of avelumab in combination with IT JX-594 and metronomic cyclophosphamide Efficacy will be defined based on objective response under treatment following RECIST v1.1 criteria

  Objective response is defined as complete or partial response as per RECIST v1.1

  Phase II : 6 months after the beginning of treatment

Secondary Outcomes (41)

• Phase Ib : Recommended Phase II dose (RP2D) of the association of JX-594 and metronomic cyclophosphamide

  Phase Ib : Throughout the 6 months of treatment period

• Phase Ib: Objective response under treatment as per RECIST V1.1

  an average of 6 months

• Phase Ib: Best overall response as per RECIST V1.1

  an average of 6 months

• Phase Ib: 6-months non-progression as per RECIST V1.1

  6-months after the beginning of treatment

• Phase Ib: 1-year progression-free survival as per RECIST V1.1

  1-year after the beginning of treatment

Study Arms (6)

Experimental phase I dose escalating

EXPERIMENTAL

Prospective open-labeled phase I trial. Combination of cyclophosphamide and JX-594 dose escalation. Metronomic cyclophosphamide will be administered orally, 50 mg twice daily, one week on/one week off. JX-594 will be administered, as designated by assigned dose-level, intraveinously, on Days 8 and 22 of cycle 1, and on days 8 of each subsequent cycles. One cycle consits of 28 days. Number of subjects : 14

Drug: Cyclophosphamide and JX-594 dose escalation

Experimental group soft-tissue sarcoma, treatment by JX-594 + Metronomic cyclophosphamide

EXPERIMENTAL

Randomized non comparative phase II clinical trial : Arm 1. Experimental phase II soft-tissue sarcoma : Combination of cyclophosphamide and JX-594. Metronomic cyclophosphamide will be administered orally, 50 mg twice daily, one week on/one week off. JX-594 will be administered, as the dose recommended in the experimental phase I dose escalating study, intraveinously, on Days 8 and 22 of cycle 1, and on days 8 of each subsequent cycles. One cycle consits of 28 days. Number of subjects : 48

Drug: Cyclophosphamide and JX-594

Control group soft-tissue sarcoma, treatment by JX-594 + Metronomic cyclophosphamide

EXPERIMENTAL

Randomized non comparative phase II clinical trial : Arm 2. Control-arm phase II soft-tissue sarcoma : Patients will be treated by metronomic cyclophosphamide. Cyclophosphamide will be administered 50 mg twice daily orally, one week on/one week off. One cycle consits of 28 days. Number of subjects : 24

Drug: Cyclophosphamide

Experimental group breast cancer, treatment by JX-594 + Metronomic cyclophosphamide

EXPERIMENTAL

Single-arm phase II clinical trial. Experimental phase II Group breast cancer : Combination of cyclophosphamide and JX-594. Metronomic cyclophosphamide will be administered orally, 50 mg twice daily, one week on/one week off. JX-594 will be administered, as the dose recommended in the experimental phase I dose escalating study, intraveinously, on Days 8 and 22 of cycle 1, and on days 8 of each subsequent cycles. One cycle consits of 28 days. Number of subjects : 32

Drug: Cyclophosphamide and JX-594

Experimental group soft-tissue sarcoma, treatment by Avelumab + ITJX-594 + Metronomic CP

EXPERIMENTAL

Experimental phase II soft-tissue sarcoma : Combination of avelumab in combination with intratumoral JX-594 and metronomic cyclophosphamide. Avelumab will be administered by intravenous infusion every 2 weeks, starting at Day 15 of cycle 1. Cyclophosphamide wil be administered orally, 50 mg twice daily, one Week on/one Week off, starting 7 days prior to cycle 1 day 1 ("impregnation phase"). JX-594 will be administered by intratumoral injection on day 1 of cycle 1, every 2 weeks, for a maximum of 4 injections. Number of subjects : 47

Drug: Avelumab and JX-594 and Cyclophosphamide

Experimental group breast cancer, treatment by Avelumab + IT JX-594 + Metronomic CP

EXPERIMENTAL

Experimental phase II breast cancer : Combination of avelumab in combination with intratumoral JX-594 and metronomic cyclophosphamide. Avelumab will be administered by intravenous infusion every 2 weeks, starting at Day 15 of cycle 1. Cyclophosphamide wil be administered orally, 50 mg twice daily, one Week on/one Week off, starting 7 days prior to cycle 1 day 1 ("impregnation phase"). JX-594 will be administered by intratumoral injection on day 1 of cycle 1, every 2 weeks, for a maximum of 4 injections. Number of subjects : 32

Drug: Avelumab and JX-594 and Cyclophosphamide

Interventions

Cyclophosphamide and JX-594 dose escalation DRUG

Metronomic cyclophosphamide will be administered orally, 50 mg twice daily, one week on/one week off. JX-594 will be administered, as designated by assigned dose-level, intraveinously, on Days 8 and 22 of cycle 1, and on days 8 of each subsequent cycles. One cycle consits of 28 days.

Also known as: Brand name : ENDOXAN, Brand name: Pexa-Vec

Experimental phase I dose escalating

Cyclophosphamide and JX-594 DRUG

Metronomic cyclophosphamide will be administered orally, 50 mg twice daily, one week on/one week off. JX-594 will be administered, as the dose recommended in the experimental phase I dose escalating study, intraveinously, on Days 8 and 22 of cycle 1, and on days 8 of each subsequent cycles. One cycle consits of 28 days.

Also known as: Brand name : ENDOXAN, Brand name: Pexa-Vec

Experimental group breast cancer, treatment by JX-594 + Metronomic cyclophosphamide; Experimental group soft-tissue sarcoma, treatment by JX-594 + Metronomic cyclophosphamide

Cyclophosphamide DRUG

Metronomic cyclophosphamide will be administered orally, 50 mg twice daily, one week on/one week off.

Also known as: Brand name : ENDOXAN

Control group soft-tissue sarcoma, treatment by JX-594 + Metronomic cyclophosphamide

Avelumab and JX-594 and Cyclophosphamide DRUG

Avelumab will be administered by intravenous infusion (10 mg/kg) every 2 weeks, starting at Day 15 of cycle 1. Cyclophosphamide wil be administered bi-daily (50 mg x 2), starting 7 days prior to cycle 1 day 1 ("impregnation phase") and given on a week on/week off schedule. JX-594 will be administered by intratumoral injection (1 x109 p.f.u) on day 1 of cycle 1, every 2 weeks, for a maximum of 4 injections .

Also known as: Brand name: ENDOXAN, Brand name: Pexa-Vec, Brand name: Avelumab

Experimental group breast cancer, treatment by Avelumab + IT JX-594 + Metronomic CP; Experimental group soft-tissue sarcoma, treatment by Avelumab + ITJX-594 + Metronomic CP

Eligibility Criteria

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

You may qualify if:

• Histology:
• Phase Ib : Patient with histologically confirmed solid tumor
• Phase II :
• Patients with histologically confirmed HER2 negative breast cancer (treatment by CP+JX-594), or triple negative (treatment by avelumab + CP+JX-594)
• Metastatic or unresectable locally advanced disease
• Age ≥ 18 years
• ECOG ≤ 1 (Phase Ib), ≤ 2 (Phase II JX+CP) and ≤ 1 (Phase II avelumab+JX+CP).
• Life expectancy \> 3 months,
• Measurable disease according to RECIST v1.1 outside any previously irradiated field. For patients treated by avelumab+JX+CP, at least one injectable site ≥ 2 cm and ≤ 8 cm in diameter and one distant non-injected measurable site (target site)
• At least three weeks since last chemotherapy, immunotherapy or any other pharmacological treatment and/or radiotherapy.
• Adequate hematological, renal, metabolic and hepatic functions.
• Women of childbearing potential must have a negative serum pregnancy test before study entry. Both women and men must agree to use a medically acceptable method of contraception throughout the treatment period and for six months after discontinuation of treatment.
• Patients informed of risks regarding drug interactions: patients receiving any substances that are inhibitors or inducers of CYP450 2B6 are ineligible
• Voluntarily signed and dated written informed consent prior to any study specific procedure.
• Patients with a social security in compliance with the French law.

You may not qualify if:

• Previous treatment with JX-594 or other vaccina vector based treatment .
• Concomitant diseases/conditions (non exhaustive list):
• Clinically significant immunodeficiency, such as HIV or active Hepatite B or C
• Any other major illness that, in the Investigator's judgment, will substantially increase the risk associated with the patient's participation in this study.
• History of severe exfoliative skins condition requiring systemic treatment for more than 4 weeks in the last two years.
• active autoimmune disease for patients treated by avelumab
• Active central nervous system metastasis (CNS)
• Participation to a study involving a medical or therapeutic intervention in the last 30 days.
• Previous enrolment in the present study.
• Patient unable to follow and comply with the study procedures because of any geographical, social or psychological reasons.
• Known hypersensitivity to any involved study drug or any of its formulation components.
• Use of steroids (any route of administration), interferon/pegylated interferon or ribavirin that cannot be discontinued within 14 days prior to any JX-594 dose.
• No prior malignancy except for the following: adequately treated basal or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage 1 or Stage 2 cancer from which the patient is currently in complete remission or any other cancer from which the patient has been disease-free for 3 years.
• Active cardiovascular disease, including but not limited to significant coronary artery disease (e.g. requiring angioplasty or stenting) or congestive heart failure within the preceding 12 months. (treatment by CP+JX)
• Inability to suspend treatment with anti-hypertensive medication for 48 hours prior to and 48 hours after all JX-594 treatments.

Sponsors & Collaborators

• Institut Bergonié: lead
• National Cancer Institute, France: collaborator
• Fondation ARC: collaborator
• Merck Sharp & Dohme LLC: collaborator
• Transgene: collaborator

Study Sites (1)

Institut Bergonie

Bordeaux, 33076, France

RECRUITING

MeSH Terms

Conditions

Sarcoma; Breast Neoplasms

Interventions

Cyclophosphamide; avelumab

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

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

Study Officials

• Antoine ITALIANO, MD, PhD

  Institut Bergonié

  STUDY CHAIR

Central Study Contacts

Antoine ITALIANO, MD, PhD

CONTACT

+33 524071947; a.italiano@bordeaux.unicancer.fr

Study Design

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

Study Record Dates

• First Submitted: November 19, 2015
• First Posted: December 15, 2015
• Study Start: September 18, 2015
• Primary Completion: May 1, 2023
• Study Completion: November 1, 2024
• Last Updated: February 2, 2022

Record last verified: 2022-01

Locations

FR (1)