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.
