Phase I Dose Escalation of Pazopanib Plus TH-302 in Advanced Solid Tumors
STUDY DESIGN 5.1 Study Description This open-label, non-randomized phase I trial is designed
to assess the safety, tolerability and maximum tolerated dose (MTD)/recommended phase II
dose (RPTD) of TH-302 plus pazopanib in adult subjects with advanced solid tumors.
Patients will be accrued (enrolled) at Duke University Medical Center. Accrued (enrolled)
subjects are defined as subjects who give informed consent. Approximately 50 subjects may be
enrolled to ensure the trial obtains approximately 30 evaluable subjects.
Evaluable subjects are defined as those subjects who give informed consent, meet
inclusion/exclusion screening criteria, received study drug treatment and completed the
first cycle of safety assessments or have dose limiting toxicity that precludes completing
the full cycle of assessments.
Please note that the number of accrued subjects exceeds the number of evaluable subjects for
the following reasons:
1. Screen failures: Subjects with informed consent that do not meet inclusion/exclusion
2. Treated patients: Subjects with informed consent that meet the inclusion/exclusion
criteria and received study drug treatment but did not complete the first cycle of
safety assessments for primary study end points (e.g. those subjects who have disease
progression or inter-current illness).
There will be two stages to this Phase I study. Stage 1 will be the dose escalation
component to determine safety and the recommended phase II dose (RPTD) for TH-302 plus
pazopanib combination. Dose escalation will begin with cohort 1 and continue as described in
Stage 2 will be an expanded cohort which will better describe the tolerability and toxicity
profile and (2) to further assess biomarkers related to mechanisms of the study agents. The
treatment schedule will be as follows:
Table 5.1 Cohort Doses Cohort # subjects Threshold 302 mg/m2, intravenously Days 1, 8, 15
Pazopanib mg, orally daily
- 1 3-6 240 800 Starting Dose
1. 3-6 340 800
2. 3-6 480 800
3. 3-6 575 800 Expanded Cohort 12-18 RPTD 800
Subjects will be treated on 28 day cycles after satisfying eligibility and
Intermediate dosing levels may be explored. Toxicity will be assessed every visit
and as clinically indicated. Efficacy will be assessed every 2 cycles and as
Dose Escalation and Treatment Schema
The NCI Common Toxicity Criteria version 4.0 will be used to grade adverse events.
The following adverse events will be considered dose limiting toxicity (DLT) if
occurring during the first cycle of treatment and deemed to be related to study
- Hematologic toxicity: Any grade 4 neutropenia, thrombocytopenia or anemia or grade ≥ 3
neutropenia or thrombocytopenia lasting over 7 days
- Any grade 3 thrombocytopenia associated with bleeding
- Neutropenic fever
- Nausea,Vomiting or Diarrhea grade 3 and lasting 4 days despite adequate supportive
- Grade ≥ 3 ALT or AST elevation > 7 days
- Other non-hematologic toxicity grade 3 excluding alopecia, anorexia, fatigue,
hypertension, isolated lab abnormalities (not clinically significant) and/ rare,
idiosyncratic reactions to any of the study drugs. Anorexia, fatigue and hypertension
will be considered as DLT only if they reach grade 4 or are considered unmanageable.
- Treatment delay of ≥ 14 days for cycle 2 due to unresolved toxicity
- Any treatment-related death or treatment-related hospitalization
Management and dose modifications associated with adverse events are outlined in Sections 9
Dose escalation will proceed in Stage 1 within each cohort according to the following
Number of Patients with DLT at a Given Dose Level Escalation Decision Rule 0 out of 3 Enter
3 subjects at the next dose level.
1 out of 3 Enter 3 more subjects at this dose level. < 1 out of 6 (a) Proceed to the next
dose level OR (b) This will be the recommended MTD/RPTD if at highest dose level. > 2 out of
3-6 Dose escalation will be stopped. Three (3) additional subjects will be entered at the
next lowest dose level (if only 3 subjects were treated at this level).
- 3 subjects with advanced solid tumors will be accrued at the starting dose level. If
no DLTs are seen, 3 subjects will be enrolled in the next dose level.
- Subjects will be monitored for at least one full cycle before advancement to the next
- If one of three subjects has DLT at a given dose level, then an additional three
subjects will be enrolled at that dose level.
- If 1/6 subjects experiences DLT at a given dose level, then escalation will continue to
the next dose level.
- If ≥ 2 out of 3-6 subjects have DLT at any dose level, then that dose level will be
considered to have unacceptable toxicity, and the next lower dose level will be
expanded to 6 patients. In this case, the next lower dose level will be declared as the
MTD provided ≤ 1/6 subjects have DLT (otherwise, dose will be further de-escalated).
In cases where the only toxicity seen at this lower dose level is Grade ≤ 2,
re-escalation for intermediate dosing will be considered. If there is uncertainty
about study drug attribution to DLT then re-escalation to full doses is also permitted.
- If > 33% of subjects has DLT at any dose level, then that dose level will be considered
to have unacceptable toxicity. The dose level immediately below the one with
unacceptable toxicity will be the recommended phase II dose.
- If no unacceptable toxicity is seen at the highest dose level, then the highest dosing
regimen will be considered the MTD or the phase II RPTD.
- Up to 6 subjects will be enrolled at MTD to better define tolerability and safety
before proceeding to the expanded cohort.
Endpoint Classification: Safety/Efficacy Study, Intervention Model: Single Group Assignment, Masking: Open Label
Maximal tolerated dose
To define the maximal tolerated dose (if any) and the recommended phase II doses for the combination of pazopanib plus TH-302 in patients with advanced solid tumors
Herbert I Hurwitz, MD
United States: Food and Drug Administration
|Duke Cancer Institute||Durham, North Carolina 27710|