Adenoviral Vector Monotherapy or Combination With Chemotherapy in Subjects With Recurrent/Metastatic Breast Cancer.

Phase 2

Terminated

Conditions: Breast Cancer Nos Metastatic Recurrent

Interventions: Genetic: Ad-RTS-hIL-12 and Veledimex
Drug: Palifosfamide

Registration Number: NCT01703754

Lead Sponsor: Alaunos Therapeutics

Brief Summary: Phase II, randomized, safety and efficacy study in recurrent/metastatic breast cancer with accessible lesions.

Primary End point is rate of Progression Free Survival (PFS) at the 16 week treatment time point. Hypothesis: Adenoviral vector (Ad-RTS-hIL-12) alone and in combination with chemotherapy (palifosfamide) is safe and efficacious.

Detailed Description: Multicenter, open-label, randomized study evaluating the safety and efficacy of INXN-1001 (veledimex) and INXN-2001 (Ad-RTS-hIL-12) alone and in combination with palifosfamide.

Part 1 is the safety run-in where a safety assessment will be made after 1 cycle of therapy.

Part 2, eligible subjects will be randomly assigned to active treatment Arms A or C.

Once the monotherapy (Arm A) is determined to be safe and tolerable, Part 1 combination therapy (Arm C) will begin.

Subjects should receive six cycles of study treatment, in the absence of meeting withdrawal criteria.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 12

Inclusion Criteria

Not provided

Exclusion Criteria

Subjects with human epidermal growth factor receptor 2 (HER2)/neu-positive (immunohistochemistry [IHC]) 3+ or fluorescence in situ hybridization-amplified) breast tumors who are eligible for, but who have not received HER2-targeted therapy (eg, trastuzumab)
Concomitant anticancer therapies
Prior therapies discontinuation periods:
1. Radiation within 3 weeks of enrollment
2. Chemotherapy within 4 weeks of enrollment
3. Nitrosoureas within 6 weeks of enrollment
4. Biologic therapy and/or immunomodulatory therapy, checkpoint inhibitors within 6 weeks of enrollment
5. No washout period is required for endocrine therapy
Radiation therapy encompassing >25% of bone marrow
History of bone marrow or stem cell transplantation
Any congenital or acquired condition leading to inability to generate an immune response
Immunosuppressive therapy:
1. Systemic immunosuppressive drugs including corticosteroids (prednisone equivalent >10 mg/day)
2. Immune suppression/requiring immunosuppressive drugs, including organ allografts
3. Active autoimmune disease requiring the equivalent of >10 mg/day of prednisone
Major surgery within 4 weeks of study treatment
History of prior malignancy, unless the prior malignancy was diagnosed and definitively treated ≥5 years previously with no subsequent evidence of recurrence
Subjects with brain or subdural metastases, unless local therapy has completed and corticosteroids have been discontinued for this indication for ≥4 weeks before starting study treatment.
Any medications that induce, inhibit, or are substrates of cytochrome P450 (CYP450) 3A4 within 7 days prior to the first dose of study drug
Subjects with meningeal carcinomatosis
Known significant hypersensitivity to study drugs or excipients
History of malabsorption syndrome or other condition that would interfere with enteral absorption
International Normalized Ratio (INR) and activated partial thromboplastin time [PTT] <1.5 x ULN, if not therapeutically anticoagulated.
New York Heart Association (NYHA) Class II or greater congestive heart failure OR active ventricular arrhythmia requiring medication
Any other unstable or clinically significant concurrent medical condition
Localized infection at site of injectable lesion(s) requiring antiinfective therapy within 2 weeks of the first dose of study drug.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Ad-RTS-hIL-12 and veledimex	Ad-RTS-hIL-12 and Veledimex	Experimental study drug monotherapy arm (A)
Ad-RTS-hIL-12 and Palifosfamide	Ad-RTS-hIL-12 and Veledimex	Study drug combination therapy arm (C)
Ad-RTS-hIL-12 and Palifosfamide	Palifosfamide	Study drug combination therapy arm (C)

Primary Outcome Measures

Name	Time	Method
Number of Participants With Treatment-Emergent Adverse Events (TEAEs)	16 months	This measure will capture the incidence of Treatment-Emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and AEs leading to discontinuation. As per the protocol, safety and tolerability were assessed by monitoring adverse events, physical examinations, vital signs, electrocardiograms (ECGs), and clinical laboratory evaluations.
16-Week Progression-Free Survival (PFS) Rate	16 weeks	This is the primary efficacy endpoint, defined as the proportion of subjects who had not progressed or died prior to 16 weeks from the date of their first dose. Progression was determined by modified Response Evaluation Criteria in Solid Tumors

Secondary Outcome Measures

Name	Time	Method
Best Overall Response (BOR) by mRECIST v1.1	24 weeks	Best Overall Response (BOR) was determined for each evaluable subject up to their final tumor assessment. Per the modified Response Evaluation Criteria in Solid Tumors (mRECIST) v1.1, responses were defined as: Complete Response (CR), disappearance of all non-nodal target lesions and reduction in short axis of pathological lymph nodes to \<10 mm; Partial Response (PR), at least a 30% decrease in the sum of diameters of target lesions from baseline; Progressive Disease (PD), at least a 20% increase in the sum of diameters from the smallest sum recorded; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD
Estimate PFS by Modified RECIST v1.1	16 months	Progression-free survival (PFS) is the time in days from the first dose of study treatment to the first assessment on which the response is reported as disease progression or death due to any cause (whichever is first) + 1 day. Subjects withdrawing from the study will be censored at their last non-progressive disease response assessment. If a subject does not have a disease response assessment, the subject will be censored on the date of the first treatment as described above. Kaplan-Meier plots will not be presented; PFS will be listed only.
Area Under the Plasma Concentration-Time Curve From 0 to 24 Hours (AUC0-24) of INXN-1001	Cycle 1 Day 1 and Cycle 1 Day 7	The area under the plasma concentration versus time curve from time 0 to 24 hours (AUC0-24) for INXN-1001
Change From Baseline in MUC-1 Specific T-Cell Response by ELISPOT Assay	Screening and the Post-Treatment Safety Assessment visit (28 days after the last dose of study drug), with the final assessment occurring up to 7 months after the start of treatment.	To assess for a cellular immune response, the number of MUC-1 specific interferon-gamma (IFN-γ) secreting T-cells was measured from peripheral blood mononuclear cells (PBMCs) using an ELISPOT assay. Results are reported as spot-forming cells (SFC) per million PBMCs
Change From Baseline in Serum Interferon-gamma (IFN-γ) Levels	Screening, 24 hours after the first injection (Day 2), and at the Post-Treatment Safety Assessment visit, with the final assessment occurring up to 7 months after the start of treatment.	Serum levels of IFN-γ were measured by immunoassay to assess the pharmacodynamic effect of the treatment
Change From Baseline in Serum Interleukin-12 (IL-12) Levels	Screening, 24 hours after the first injection (Day 2), and at the Post-Treatment Safety Assessment visit, with the final assessment occurring up to 7 months after the start of treatment.	Serum levels of IL-12 were measured by immunoassay to assess the pharmacodynamic effect of the treatment
Change From Baseline in CD3+ CD4+ T-Cell Count	Screening, Cycle 1 the Post-Treatment Safety Assessment visit Day 28 ± 3, and Follow-Up Tumor Assessment visits Day 63 ± 7	Absolute counts of CD3+ CD4+ helper T-cells in peripheral blood were measured by flow cytometry to evaluate changes in immune cell populations.
Change From Baseline in CD3+ CD8+ T-Cell Count	Screening, Cycle 1 the Post-Treatment Safety Assessment visit Day 28 ± 3, and Follow-Up Tumor Assessment visits Day 63 ± 7	Absolute counts of CD3+ CD8+ cytotoxic T-cells in peripheral blood were measured by flow cytometry to evaluate changes in immune cell populations
Maximum Plasma Concentration (Cmax) of INXN-1001	Cycle 1 Day 1 and Cycle 1 Day 7. On Day 1, samples were collected pre-dose and at 0.5, 1, 2, 4, and 6 hours post-dose. On Day 7, samples were collected pre-dose and at 1-2 and 4-6 hours post-dose	The maximum observed plasma concentration (Cmax) of INXN-1001 following oral administration.
Time to Maximum Plasma Concentration (Tmax) of INXN-1001	Cycle 1 Day 1 and Cycle 1 Day 7	The time to reach the maximum observed plasma concentration (Tmax) of INXN-1001 following oral administration
Clinical Benefit Rate (CBR)	From the first dose of study treatment for up to 1 year.	Clinical Benefit Rate (CBR) was a pre-specified secondary endpoint defined as the proportion of subjects with a best overall response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD), as assessed by modified RECIST (mRECIST) v1.1.

Trial Locations

Locations (8): Baptist Cancer Institute
🇺🇸
Jacksonville, Florida, United States
Henry Ford Health System
🇺🇸
Detroit, Michigan, United States
Billings Clinic
🇺🇸
Billings, Montana, United States
Signal Point Clinical Research Center
🇺🇸
Middletown, Ohio, United States
Greenville Hospital System
🇺🇸
Greenville, South Carolina, United States
The Jones Clinic, PC
🇺🇸
Germantown, Tennessee, United States
Mary Crowley Medical Research Center
🇺🇸
Dallas, Texas, United States
Evergreen Hematology & Oncology
🇺🇸
Spokane, Washington, United States
Baptist Cancer Institute
🇺🇸Jacksonville, Florida, United States