A Study of Ivaltinostat Plus Capecitabine or Capecitabine in Metastatic Pancreatic Adenocarcinoma

This study is a Phase 1b/2, dose-escalation, randomized, multicenter study to assess the efficacy, safety, tolerability, and PK of ivaltinostat in combination with capecitabine and capecitabine monotherapy in patients with metastatic pancreatic adenocarcinoma whose disease has not progressed on a first line fluoropyrimidine-based chemotherapy (e.g., FOLFIRINOX).

In Phase 1b, 3 dose levels of ivaltinostat will be studied in combination with a fixed dose of capecitabine to determine the RP2D of ivaltinostat.

In Phase 2, patients will be randomized in a 1:1 ratio to the combination of ivaltinostat and capecitabine or to capecitabine monotherapy. A fixed dose for capecitabine 1000 mg/m2 orally twice daily will be taken on Days 1 to 14, and the RP2D of ivaltinostat will be administered intravenously once a week for 2 weeks, followed by 1 week of rest. One cycle consists of 21 days. Tumor response during study treatment will be assessed every 6 weeks up to Cycle 10, then every 9 weeks afterwards using RECIST v1.1 criteria.

There will be approximately 70 (18 Phase 1b dose-escalation, 52 Phase 2 randomized) patients in the study. In Phase 1b, 3 dose levels of ivaltinostat will be studied in combination with a fixed dose of capecitabine to determine the RP2D of ivaltinostat. In Phase 2, patients will be randomized in a 1:1 ratio to the combination of ivaltinostat and capecitabine or to capecitabine monotherapy as specified below:

Arm A

• Ivaltinostat (the dose will be selected after reviewing the results of Phase 1b among 3 dose levels of 60, 125, or 250 mg/m2) intravenous infusion over 60 minutes (±10 minutes) once on Days 1 and 8 of a 21-day cycle
• Capecitabine 1000 mg/m2 orally twice daily on Days 1 to 14 of a 21-day cycle OR Arm B
• Capecitabine 1000 mg/m2 orally twice daily on Days 1 to 14 of a 21-day cycle Study Assessments In Phase 1b, patients will attend clinic visits in Cycle 1 on Days 1, 2, 3, 5, 8, and 15 for assessments, with treatment on Days 1 and 8. After Cycle 1, patients will attend clinic visits on a weekly schedule for treatment (Days 1 and 8) and assessments (Days 1, 8, and 15) during 21-day cycles for the remainder of time receiving study treatment. In Phase 2, patients will attend clinic visits on a weekly schedule for treatment (Days 1 and 8) and assessments (Days 1, 8, and 15) during 21-day cycles.

The Phase 1b will enroll up to 18 patients (6 patients each of 3 dose levels of ivaltinostat [60, 125, and 250 mg/m2] + 1000 mg/m2 capecitabine BID) to assess the combination of ivaltinostat and capecitabine for safety and tolerability as well as to determine the ivaltinostat RP2D, assess the PDy of ivaltinostat, and assess PK parameters of both ivaltinostat and capecitabine. Data from the Phase 1b will be used in safety analyses but not in efficacy analyses.

Tumor response during study treatment will be assessed using RECIST v1.1 criteria. Baseline and on-treatment tumor assessments will be performed using CT or MRI scans with contrast of the chest, abdomen, and pelvis, with other regions as clinically indicated for the assessment of disease. Baseline evaluation should be performed within the 28-day screening period prior to the start of study treatment, as close as possible to randomization. Follow-up assessment consistent with baseline radiologic evaluation (i.e., if CT scan was performed for baseline assessment, then CT scan should be done for the follow-up evaluation) should be performed approximately every 6 weeks (±1 week) until objective disease progression as defined by RECIST v1.1. In addition to the imaging listed above, any other sites with known disease, or at which new disease is suspected, should also be appropriately imaged. Safety evaluations will occur at each protocol-specified study visit.

Patients will continue to receive study treatment until objective radiographic disease progression per RECIST v1.1 as assessed by the Investigator or until unacceptable toxicity occurs.

Once patients have discontinued study treatment, subsequent treatment options will be at the discretion of the treating physician. It is anticipated (but not required) that patients may be retreated with their first line regimen. Patients will be contacted on an approximately every-8-week schedule and followed up for survival. Details of any further anti-cancer treatment will be collected until death, loss to follow up, or withdrawal of consent. In addition to contact every 8 weeks, patients will be contacted in the 7 days following a specified date (data cut-off date) to capture survival status at that point for each survival analysis. Any patient who discontinues study treatment for reasons other than objective radiographic progression should continue to undergo scheduled objective tumor assessments according to the study plan in order to assess objective radiographic progression of disease.