Clinical trial NCT02641639
Conditions: Platinum Resistant Ovarian Cancer
Sponsor: Mateon Therapeutics
Start date: 2016-06-01; Completion date: 2017-10-01
Enrollment: 70 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a multicenter, multinational, randomized, double-blind, 2-arm, parallel-group, Phase 2/3 study to evaluate the efficacy and safety of PCC plus bevacizumab and CA4P versus PCC plus bevacizumab and placebo in subjects with platinum-resistant ovarian cancers (prOC). Subjects with platinum-resistant, recurrent, epithelial ovarian, primary peritoneal or fallopian tube cancer will be randomized 1:1 to receive PCC plus bevacizumab and CA4P or PCC plus bevacizumab and placebo. Subjects will be stratified by selected chemotherapy (PLD vs. paclitaxel), platinum free interval (\< 3 vs. 3 to 6 months from last platinum therapy to subsequent progression), and line of therapy (2nd vs. 3rd). This is a 2-part study, consisting of a Phase 2, exploratory study (Part 1) followed by a Phase 3, pivotal study (Part 2). Both parts of the study will have similar overall design. Approximately 80 subjects will be randomized into Part 1 and approximately 356 subjects will be randomized into Part 2.

Detailed description:
This is a multicenter, multinational, randomized, double-blind, 2-arm, parallel-group, Phase 2/3 study to evaluate the efficacy and safety of PCC plus bevacizumab and CA4P versus PCC plus bevacizumab and placebo in subjects with platinum-resistant ovarian cancers (prOC). Subjects with platinum-resistant, recurrent, epithelial ovarian, primary peritoneal or fallopian tube cancer will be randomized 1:1 to receive PCC plus bevacizumab and CA4P or PCC plus bevacizumab and placebo. Subjects will be stratified by selected chemotherapy (PLD vs. paclitaxel), platinum free interval (\< 3 vs. 3 to 6 months from last platinum therapy to subsequent progression), and line of therapy (2nd vs. 3rd). This is a 2-part study, consisting of a Phase 2, exploratory study (Part 1) followed by a Phase 3, pivotal study (Part 2). Both parts of the study will have similar overall design. Approximately 80 subjects will be randomized into Part 1 and approximately 356 subjects will be randomized into Part 2.

All subjects randomized will receive bevacizumab 10 mg/kg intravenously (IV) on Days 1 and 15, repeated every 4 weeks (q4wk) and PCC with paclitaxel 80 mg/m2 IV on Days 1, 8, 15 and 22, repeated q4wk, or paclitaxel 80 mg/m2 IV on Days 1, 8, 15, repeated q4wk or PLD 40 mg/m2 IV on Day 1, repeated q4wk. Subjects in the Treatment Arm will also receive CA4P 60 mg/m2 on the same day as bevacizumab (Days 1 and 15, repeated q4wk), while subjects in the Control Arm will receive placebo on those days.

Order of dosing will follow the guidance listed below during this study when bevacizumab and CA4P / Placebo are dosed the same day as PCC,

* Bevacizumab followed by CA4P / Placebo followed after 1-3 hours by paclitaxel,
* PLD followed by bevacizumab followed by CA4P / Placebo Subjects will continue randomized treatment until disease progression, unacceptable toxicity, investigator decision, withdrawal of consent, or sponsor discontinues study for any reason. Subjects will undergo tumor assessments (RECIST) at baseline and every 8 weeks and CA-125 levels at baseline and every 4 weeks.

The primary endpoint is PFS. Secondary endpoints include ORR, OS, proportion of subjects who remain progression free at 6, 9, and 12 months, and safety. Endpoints will be compared between the Treatment Arm and the Control arm. The study duration is estimated to last approximately 3 years.

This study will have 2 parts with the same overall design. Part 1 will enroll up to approximately 80 subjects and will include multiple interim analyses to test the safety and efficacy assumptions in this specific subject population. Upon meeting certain efficacy criteria in Part 1, the protocol will be amended and additional sites added in order to enroll an additional 356 subjects into Part 2 of the study. Subjects enrolled in Part 2 will be analyzed separately and used as a stand-alone confirmatory efficacy study.

Arms: arm 1: Physician's choice chemotherapy (weekly Paclitaxel or Pegylated Liposomal Doxorubicin \[PLD\]) plus bevacizumab and CA4P arm 2: Physician's choice chemotherapy (weekly Paclitaxel or Pegylated Liposomal Doxorubicin \[PLD\]) plus bevacizumab and placebo
Interventions: intervention 1: Fosbretabulin tromethamine intervention 2: Placebo
Intervention descriptions: intervention 1: CA4P is a synthetic phosphorylated prodrug of CA4, a naturally occurring derivative of the South African willow tree, combretum caffrum. CA4P targets pre-existing tumor vasculature, resulting in an acute, reversible reduction in TBF that leads to central necrosis within tumors. intervention 2: Saline for infusion

Protocol documents:
Prot_SAP_000.pdf: 
OX4325 (FOCUS): A Multicenter, Multinational, Double-blind, 2-Arm, 
Randomized, Phase 2/3, Study of Physician’s Choice Chemotherapy (PCC) (Weekly 
Paclitaxel or Pegylated Liposomal Doxorubicin [PLD]) Plus Bevacizumab and 
CA4P Versus PCC Plus Bevacizumab and Placebo for Subjects with Platinum-
Resistant, Recurrent, Epithelial Ovarian, Primary Peritoneal or Fallopian Tube 
Cancer 
 
NCT: NCT02641639 
 
Protocol Amendment Date: 21 March 2017 












 
 
  
 
  
 
 
 
  
 
 
criteria, will be performed during screening and repeated every 8 weeks from dosing using the 
same assessment technique used at baseline (CT or magnetic resonance imaging [MRI]).  
Assessment of PFS will be based on the principal investigator’s (PI’s) or qualified individuals 
(thru experience or training) assessment, but scans will be collected for possible additional 
review. 
Secondary endpoints include ORR, OS and the proportion of progression-free subjects at 6, 9 
and 12 months. The ORR will be defined as the proportion of subjects with a confirmed 
complete response (CR) or confirmed partial response (PR) per RECIST 1.1 criteria, based 
upon the best response. The ORR will be determined based on investigator assessment 
according to RECIST 1.1 criteria and/or GCIG CA-125 criteria. Overall survival is defined as 
the time from randomization to the date of death from any cause. The proportion of 
progression-free subjects at 6, 9 and 12 months will be based on the number of evaluable 
subjects at each time point who have not progressed per investigator or qualified individual 
assessment using RECIST 1.1. 
Safety: 
Safety and tolerability will be measured by physical exams, vital signs, laboratory measures, 
ECOG PS, and incidence of AEs using the NCI CTCAE version 4.03. Safety summaries will 
be reviewed by Data Safety Monitoring Committee (DSMC) during the defined interim 
analyses of Part 1, including analysis of certain AEs of Special Interest that will be outlined in 
the Statistical Analysis Plan. The DSMC will consist of Mateon employees and consultants 
with meetings post each interim analysis to review safety summaries and AEs of special 
interest data. An Independent Data Monitoring Committee (IDMC) will be established to 
review the safety data summaries and examine the findings of the interim futility analysis in 
Part 2. The IDMC will consist of an independent statistician and two independent physicians 
with meetings to review study safety summaries and analyze AEs of special interest data. 
Details on the review will be established in a DMC charter, to be completed prior to initiation 
of Part 2 of the study. 
Statistical methods:  
Primary Efficacy Variable: 
PFS is the primary efficacy endpoint and is defined as the time from the date of randomization 
to disease progression or death from any cause. Subjects will be followed until their date of 
death, loss to follow-up, withdrawal of consent for further follow-up for survival, or final 
database closure. 
Subjects who are lost-to-follow-up or are not known to have disease progression at the time of 
data- cut-off for analysis will be censored at last date shown to be alive.  Subjects who do not 
have any follow up since randomization will be censored at the date of randomization. 
The primary efficacy analysis of PFS will be based on the intent-to-treat (ITT) population, 
using a stratified 2-sided log-rank test to test the hypothesis of equality of the survival curves 
between groups 
(0.05 significance level). Kaplan-Meier estimates of the survival curves and the median 
survival times and their corresponding 95% confidence interval (CI) will be presented by 
Mateon Therapeutics
______________________________________________________________________________________________
Fosbretabulin tromethamine (Combretastatin A4-Phosphate, CA4P)
Protocol No. OX4325 (Amendment 6)
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treatment group. Cox’s proportional hazards regression model will also be used to compare 
hazard rates between the 2 treatment groups, adjusting for selected chemotherapy (PLD vs. 
paclitaxel), platinum free interval (< 3 vs. 3 to 6 months from last platinum therapy to 
subsequent progression), and line of therapy (2nd vs. 3rd / 4th). The hazard ratio (HR) and its 
95% CI will be calculated. 
The robustness of the principal analysis of PFS described above will be examined through 
sensitivity analyses that will be considered supportive to the principal analysis.  The suggested 
sensitivity analysis only includes well-documented and verifiable progression events. 
Subgroup analyses of PFS will be performed to assess whether the treatment effect is 
concordant among subgroups.  The planned subgroup analyses are based on age categorization 
(ages < 40 years, 
40- < 65 years, and ≥ 65 years), selected chemotherapy (PLD vs. paclitaxel), platinum free 
interval (<  3 vs. 3 to 6 months from last platinum therapy to subsequent progression), and line 
of therapy (2nd vs. 3rd / 4th), ECOG status at baseline (0 vs. ≥ 1), race (White, Black, Asian, and 
other), and time from initial diagnosis to randomization (< 2 vs. ≥ 2 years). 
Secondary Efficacy Variables: 
The ORR will be assessed at each radiographic assessment by the investigator or qualified 
individual using the following criteria: 
 By RECIST only (“RECIST Responders”) 
 By RECIST and CA-125 response criterion (“Responders”) 
 By CA-125 response criterion only (“CA-125 Responders”) 
The ORR will be defined as the proportion of subjects with a CR or a PR per RECIST based 
upon the best response as assessed; confirmation of response is not required. 
The ORR will be analyzed using The Cochran-Mantel-Haenszel (CMH) test stratified by the 
randomization stratification factors to assess the significance of the treatment effect on ORR.  
The treatment effect on ORR will be quantified using the odds ratio.  Clopper-Pearson 2-sided 
95% 
confidence limits will be calculated for the proportion of subjects with ORR in each group. 
The ORR analyses will be performed for the Efficacy Evaluable population.  Subjects who do 
not have measurable disease at baseline will be excluded from the population. 
In addition to representing ORR, the best response using response categories CR, PR, stable 
disease 
(SD), progressive disease (PD), and not evaluable (NE) will be tabulated. The proportion of 
the response in each response category will be calculated.  Subjects who do not have any post-
baseline tumor assessment will be counted under the NE category. 
Safety Variables: 
The safety data will include AEs, serious adverse events (SAEs), ECOG PS, clinical laboratory 
tests, vital signs and physical examination results. Summaries will use the Safety Population 
and will be presented separately for subjects in the Treatment Arm and Control Arm.  All 
Mateon Therapeutics
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Fosbretabulin tromethamine (Combretastatin A4-Phosphate, CA4P)
Protocol No. OX4325 (Amendment 6)
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of the study.  If proof of concept is achieved in Part 1, the study will continue to Part 2.  
Subjects in Part 1 will not be included in the Part 2 efficacy analysis, but will be followed for 
up to 10 months. 
A futility interim analysis in Part 2 is planned when approximately 50% of PFS total events are 
observed. The total PFS events required is approximately 238. 
 
 
 
______________________________________________________________________________________________
Fosbretabulin tromethamine (Combretastatin A4-Phosphate, CA4P)
Protocol No. OX4325 (Amendment 6)
______________________________________________________________________________________________