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Cyclophosphamide

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Adjuvants, Immunologic

Patients receive cyclophosphamide IV over 30 minutes on day 1, pegfilgrastim SC on day 2, and TLR8 agonist VTX-2337 SC on day -6 of course 1 only and on days 9 and 16. Patients achieving CR, PR, or SD may continue therapy every 21 days for 3 additional courses. Treatment may then continue in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Pegfilgrastim

Pharmacological Study

TLR8 Agonist VTX-2337

Peter Cohen

This phase Ib trial studies the best way of TLR8 Agonist VTX-2337 and cyclophosphamide in treating patients with a solid tumor that has spread from the primary site (place where it started) to other places in the body (metastatic), progressed for a long time (persistent), come back (recurrent), or is growing, spreading, or getting worse (progressed). TLR8 Agonist VTX-2337 may stimulate the immune system in different ways and stop tumor cells from growing. Drugs used in chemotherapy, such as cyclophosphamide, 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. Giving TLR8 Agonist VTX-2337 together with cyclophosphamide may be a better treatment for solid tumors.

PRIMARY OBJECTIVES:

I. To assess the ability of a dosing schedule of cyclophosphamide, pegfilgrastim, and TLR8 agonist VTX-2337 (CyNeuMoto) to reproducibly immunomodulate patients in a manner which enhances the endogenous antitumor effector response.

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of this treatment by assessing the adverse events.

II. Best overall response rate, as assessed by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST) criteria (irBORR).

III. Duration of tumor response, as assessed by irRECIST (irDOR). IV. Progression-free survival (PFS) as measured by serial imaging studies and assessed by irRECIST.

V. Overall survival, as measured by subject vital status for 36 months following discontinuation of study treatment.

TERTIARY OBJECTIVES:

I. To test the hypothesis that this regimen will prove efficacious as an immunomodulator regardless of the number of prior chemotherapy (chemo) regimens or type of cancer assessed.

II. To evaluate baseline immune status in patients (peripheral blood and intratumoral effector T cells, regulatory T cells, tumoricidal monocytes, and myeloid-derived suppressor cells) as well as the modulatory effects of the treatment upon individual immune components.

III. To correlate treatment-induced immune modulations to clinical outcomes (overall response rate \[ORR\], progression-free survival \[PFS\] as determined by immune-related RECIST \[irRECIST\], and overall survival).

IV. To correlate treatment-induced immune modulations and clinical outcomes to the magnitude of leukopenia (and its surrogate, neutropenia) achieved by the treatment.

OUTLINE:

Patients receive cyclophosphamide intravenously (IV) over 30 minutes on day 1, pegfilgrastim subcutaneously (SC) on day 2, and TLR8 agonist VTX-2337 SC on day -6 of course 1 only and on days 9 and 16. Patients achieving complete response (CR), partial response (PR), or stable disease (SD) may continue therapy every 21 days for 3 additional courses. Treatment may then continue in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 36 months.

TLR8 Agonist VTX-2337 and Cyclophosphamide in Treating Patients With Metastatic, Persistent, Recurrent, or Progressive Solid Tumors

Phase IB Study Investigating the Tolerability, Immunomodulatory Impacts and, Therapeutic Correlates of the Novel Toll-like Receptor 8 Agonist Motolimod (MOTO) Plus Cyclophosphamide (CTX) Treatment of Advanced Solid Tumors

Assessed over time using graphical and statistical methods overall and by treatment course. Changes over time will be assessed using paired t-tests (or the nonparametric equivalent), where changes from baseline and/or course 11 (run-in phase) will be compared to various timepoints of interest post-course 1 (course 2, course 3, etc.). Changes in markers will be assessed by patient groups of interest (i.e. cancer type and the number of prior chemotherapy regimens). Tumor and immune markers will be correlated with clinical endpoints like response, progression-free survival, overall survival, and

The pharmacodynamics after TLR8 agonist VTX-2337 alone will be compared to TLR8 agonist VTX-2337+cyclophosphamide to test the hypothesis that TLR8 agonist VTX-2337+cyclophosphamide (course 2) will be significantly more immunomodulatory than TLR8 agonist VTX-2337 alone (course 1 run in dose) in regards to (1) reducing % and absolute numbers of Tregs compared to total lymphocytes; (2) reducing absolute numbers of MDSCs; (3) increasing % of total peripheral T cells activatable to produce IFNg; and (4) increasing % of total peripheral monocytes activatable to produce nitric oxide or express induci

The distribution of duration of response will be estimated using the method of Kaplan-Meier. Supplemental statistical analysis will include comparison of the duration of response between groups of interest using a Cox proportional hazards model. As an exploratory analysis, will also determine if patients who achieve sustained intratreatment responses (defined as disease stabilization or a maximum objective response unchanged over six cycles of treatment) continue to maintain this response upon cessation of treatment.

The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine adverse event patterns using CTCAE version 4.0.

The distributions of OS will be estimated using Kaplan-Meier methodology and will be compared between groups of interest using a log-rank test. Supplemental statistical analysis will include comparison of the OS between groups of interest using a Cox proportional hazards model.

The distribution of PFS will be estimated using Kaplan-Meier methodology. Supplemental statistical analysis will include comparison of the PFS between groups of interest using a Cox proportional hazards model.

National Cancer Institute (NCI)

Mayo Clinic

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
TLR8 Agonist VTX-2337 and Cyclophosphamide in Treating Patients With Metastatic, Persistent, Recurrent, or Progressive Solid Tumors	NCT02650635	Colorectal Aden... Metastatic Panc... Recurrent Breas... Recurrent Color... Recurrent Melan... Recurrent Non-S... Recurrent Pancr... Recurrent Renal... Solid Neoplasm Stage IV Breast... Stage IV Non-Sm... Stage IV Renal ... Stage IV Skin M... Stage IVA Color... Stage IVA Pancr... Stage IVB Color... Stage IVB Pancr...	Cyclophosphamid... Laboratory Biom... Pegfilgrastim Pharmacological... TLR8 Agonist VT...	18 Years -	Mayo Clinic
TLR8 Agonist VTX-2337 and Cyclophosphamide in Treating Patients With Metastatic, Persistent, Recurrent, or Progressive Solid Tumors	NCT02650635	Colorectal Aden... Metastatic Panc... Recurrent Breas... Recurrent Color... Recurrent Melan... Recurrent Non-S... Recurrent Pancr... Recurrent Renal... Solid Neoplasm Stage IV Breast... Stage IV Non-Sm... Stage IV Renal ... Stage IV Skin M... Stage IVA Color... Stage IVA Pancr... Stage IVB Color... Stage IVB Pancr...	Cyclophosphamid... Laboratory Biom... Pegfilgrastim Pharmacological... TLR8 Agonist VT...	18 Years -	Mayo Clinic

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