Fallopian Tube Cancers, Peritoneal Carcinoma, Platinum Resistant Ovarian Cancer
Conditions
Brief summary
This is an open-label, Phase 1 clinical study to evaluate the safety, tolerability, PK profiles, and clinical activity of IV and PO arginine supplementation + SOC chemoimmunotherapy regimens in participants with PROC.
Detailed description
This is a Phase I, investigator-initiated and open-label study. Patients will be evaluated and treated at University of Alabama Birmingham Hospital. Patients will receive both oral and IV arginine with the physician choice of paclitaxel, pembrolizumab, +/- bevacizumab or pembrolizumab, bevacizumab, and oral cyclophosphamide, where doses and schedule are consistent with standard of care. Patients who are excluded from the trial due to progression will be scheduled for three- and six-months follow-up evaluations after the last dose. The goal for enrollment will be 6-24 patients with a 3-patient safety dose escalation lead-in using a 3+3 enrollment model for each regimen.
Interventions
DRUGCohort A1
Weekly paclitaxel + q3w pembrolizumab +/- bevacizumab + 4.5g daily oral arginine
DRUGCohort A2
Weekly paclitaxel + q3w pembrolizumab +/- bevacizumab + q3w 30g IV arginine
DRUGCohort A3
Weekly paclitaxel + q3w pembrolizumab +/- bevacizumab + q3w 30g IV arginine + 4.5g daily PO arginine
DRUGA3 Expansion
Continue - Weekly paclitaxel + q3w pembrolizumab +/- bevacizumab + q3w 30g IV arginine + 4.5g daily PO arginine
DRUGCohort B1
q3w IV bevacizumab + q3w IV pembrolizumab + daily oral phosphamide + 4.5g daily oral arginine
DRUGCohort B2
q3w IV bevacizumab + q3w IV pembrolizumab + daily oral phosphamide + 30mg IV arginine
DRUGCohort B3
q3w IV bevacizumab + q3w IV pembrolizumab + daily oral phosphamide + 30mg IV arginine + 4.5g PO arginine
DRUGB3 Expansion
Continue - q3w IV bevacizumab + q3w IV pembrolizumab + daily oral phosphamide + 30mg IV arginine + 4.5g PO arginine
Sponsors
Rebecca Arend
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
FEMALE
Age
18 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
1. Must be at least 18 years of age 2. ECOG performance status of 0 or 1 (see Appendix A). 3. Patient must be a candidate for either cohort A or cohort B treatment backbone. * For patients enrolling on treatment cohort A, PD-L1 positivity must be ≥1. Patient's with PD-L1 positivity ≥1% can enroll in cohort B at physician's discretion. * If PD-L1 positivity is unavailable or is \<1%, patients can only enroll on treatment cohort B. 4. Patients must have high-grade serous or endometrioid histology 5. Recovery to baseline or ≤ Grade 1 CTCAE v.5.0 from toxicities related to the prior therapy, unless after discussion with the medical monitor the AE(s) are deemed clinically non-significant and/or stable on supportive therapy 6. Participant must be able to understand the study procedures and agree to participate in the study by providing written informed consent 7. Patients must have adequate hematologic, liver and kidney functions prior to lead-in chemotherapy defined as: 1. Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L (1,500/μL) 2. Platelet count ≥ 100 x 109 /L (100,000/μL) without platelet transfusion in the prior 10 days 3. Hemoglobin ≥ 9.0 g/dL 4. Serum creatinine ≤ 1.5 x upper limit of normal (ULN) 5. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3.0 x ULN 6. Serum bilirubin ≤ 1.5 x ULN (patients with documented diagnosis of Gilbert syndrome are eligible if total bilirubin \< 3.0 x ULN) 7. Serum albumin ≥ 2 g/dL.
Exclusion criteria
1. History of allergic reactions contributed to compounds of similar chemical or biological composition to R-Gene 10 or Arginaid. 2. Patient unwilling/unable to receive daily arginine treatment (IV or oral) 3. Patients with a history of serologically confirmed HSV-1 or HSV-2 outbreaks 4. Receiving systemic corticosteroids or have severe comorbities where treatment with corticosteroids may be required. 5. Actively treated auto-immune disease. 6. Taking medications that interfere with the urea cycle such as valproate or xanthine oxidase inhibitors. 7. Current intercurrent illnesses including active infection, symptomatic congestive heart failure, unstable angina, or cardiac arrhythmias. 8. Patients with history of Peptic Ulcer Disease 9. Contraindications to receive standard of care treatment backbone with either paclitaxel, bevacizumab, pembrolizumab, or cyclophosphamide.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Proportion of patients with serious adverse events | Baseline through year 2 | This measures the proportion of patients experiencing serious adverse events |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate | Baseline through year 2 | Tumor burden will be evaluated in all participants by the investigator at screening and during/after the intervention period per RECIST 1.1 guidelines. Based on changes in tumor burden, participants will be classified as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or not evaluable (NE). Participants who are classified as CR or PR will be defined as responders. The overall response rate (ORR) is the proportion of responders out of the evaluable participants. ORR = (PR + CR)/(PR + CR+ SD+ PD) |
| Duration of Response | Baseline through year 2 | Duration of response (DOR) is a time-to-event endpoint measured only in participants who respond to treatment. DOR is the time between response to treatment and disease progression or death. Patients who are lost to follow-up before disease progression or death are censored at time of last contact. |
| Disease control rate | Baseline through year 2 | Tumor burden will be evaluated in all participants by the investigator at screening and during/after the intervention period per RECIST 1.1 guidelines. Based on changes in tumor burden, participants will be classified as complete response (CR), partial response (PR), stable disease (SD), progressive disease (PD), or not evaluable (NE). Participants who are classified as CR, PR or SD will be defined as having disease control. The disease control rate (DCR) is the proportion of participants with disease control out of the evaluable participants. DCR = (PR + CR + SD)/(PR + CR+ SD+ PD) |
| Progression Free Survival | Baseline through year 2 | Progression free survival (PFS) is a time-to-event endpoint. PFS is the time between start of treatment and the earlier of disease progression or death. Patients who are lost to follow-up before disease progression or death are censored at time of last contact. |
| Overall Survival | Baseline through year 2 | Overall survival (OS) is a time-to-event endpoint. OS is the time between start of treatment and death. Patients who are lost to follow-up before death are censored at time of last contact. |
Countries
United States
Contacts
CONTACTRebecca C Arend, MD
CONTACTRebecca A Arend
PRINCIPAL_INVESTIGATORRebecca C Arend, MD
The University of Alabama at Birmingham
Outcome results
None listed