Clinical trial NCT02641639: FOCUS: PCC + Bevacizumab + CA4P Versus PCC + Bevacizumab + Placebo for Subjects With Platinum Resistant Ovarian Cancer
Official title: 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
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE2
PHASE3
Conditions: Platinum Resistant Ovarian Cancer
Lead sponsor: Mateon Therapeutics
Sponsor class: INDUSTRY
First posted: 2015-12-29
Enrollment: 70
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion:

1. Signed informed consent form (ICF)
2. Age ≥ 18 years (Age ≥ 19 years if required by local regulatory authorities)
3. ECOG PS of 0-1
4. Histologically or cytologically-confirmed epithelial ovarian, fallopian tube or primary peritoneal cancer in recurrent stage
5. prOC (platinum-resistant ovarian cancers) defined as progression within \> 1 to \< 6 months (+ 2 weeks) of completing previous cycle of primary platinum-based therapy, or during or within \< 6 months (+ 2 weeks) of starting additional platinum based therapies
6. Received ≥ 1 but ≤ 3 prior platinum-based regimens
7. Measurable disease according to RECIST 1.1
8. Left ventricular ejection fraction (LVEF) greater than or equal to at least 45% at baseline assessment if subject is receiving PLD, and/or anthracycline is a concomitant medication
9. No evidence of active (progressing) brain metastasis. (Treated brain metastasis allowed with a posttreatment magnetic resonance imaging (MRI) or Computed Tomography (CT) of brain showing no active (progressing) brain metastasis). Treatment of brain metastasis may include surgery, radiosurgery (linear accelerator (LINAC), gamma knife), or whole brain irradiation. Surgery for brain metastasis must be \> 8 weeks from study entry
10. Hemoglobin \> 9 g/dl. Erythroid growth factors should not have been used in the 2 weeks prior to study entry. Red blood cell transfusions are permitted to maintain the hemoglobin level \> 9 g/dl
11. Adequate bone marrow function in the investigator's opinion
12. Adequate hepatic function defined by the following:

    * Total bilirubin \< 2 x Upper Limit of Normal (ULN)
    * Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) \< 2.5 X ULN for the referenced lab (\< 5 X ULN for subjects with liver metastases)
13. Adequate renal function defined by the following:

    - Serum creatinine \< 2 X ULN for the referenced lab
14. Subjects of childbearing potential must have a negative serum pregnancy test prior to study entry and must be practicing a highly effective form of contraception
15. At least 2 weeks since prior radiotherapy and has recovered from any Grade 3 toxicities
16. Life expectancy ≥ 12 weeks

Exclusion:

1. Subjects who have received prior CA4P therapy
2. Previously having failed treatment with bevacizumab combined with the intended PCC.

   - For clarity: Investigators should not select a bevacizumab + PCC combination for the FOCUS trial if the patient has previously failed that same regimen, however they may select a new PCC regimen to combine with bevacizumab. For example, a patient who failed bevacizumab + weekly paclitaxel would be allowed to enroll in FOCUS only if they are assigned to bevacizumab + PLD for the study.
3. Previous treatment with greater than three traditional chemotherapy treatment regimens
4. Untreated brain metastasis or leptomeningeal brain metastasis
5. Solid organ or bone marrow transplant
6. Primary platinum-refractory disease (defined as progression during dosing or within one (1) month of completing the last cycle of patients first platinum-containing regimen)
7. \> Grade 2 peripheral neuropathy
8. Current thrombotic or hemorrhagic disorder/event or history of prior event within 6 months of start of Screening
9. History of prior cerebrovascular event, (including transient ischemic attack) within 6 months of start of Screening
10. Recent history (within 6 months of start of Screening) of angina pectoris, myocardial infarction (including non-Q wave MI), or NYHA Class III and IV congestive heart failure
11. History of torsade de pointes, ventricular tachycardia or fibrillation, pathologic sinus bradycardia (\<60 bpm), heart block (excluding 1st degree block, benign PR interval prolongation only), congenital long QT syndrome or new ST segment elevation or depression or new Q wave on ECG
12. Known uncontrolled HIV infection
13. Uncontrolled, clinically significant active infection
14. Serious non-healing wound, ulcer or bone fracture
15. Subjects with known hypersensitivity to any of the components of CA4P, paclitaxel, PLD, or bevacizumab (paclitaxel and PLD dependent on whether PI plans they will be dosed with that PCC)
16. Subjects who are currently or planning on receiving concurrent investigational therapy or who have received investigational therapy for any indication within 30 days of the first scheduled day of dosing
17. Subjects with any other intercurrent medical condition, including mental illness or substance abuse, deemed by the Investigator to be likely to interfere with a subject's ability to provide informed consent, cooperate and participate in the study, or to interfere with the interpretation of the study results
18. Subjects with other invasive malignancies, with the exception of non-melanoma skin cancer, or with previous cancer treatment that contraindicates this protocol therapy within last 3 years
19. Prior radiation therapy to the pelvis or abdomen within 4 weeks of entry into the study
20. History of fistula, gastrointestinal (GI) perforation or intra-abdominal abscess, or invasive disease/metastases of the bowel which in the investigators opinion may increase the risk of GI perforation with bevacizumab treatment.
21. Uncontrolled hypertension (HTN)

    - Sustained BP greater than 150 mmHG SBP / 100 mmHG DBP
22. Uncontrolled elevated proteinuria levels in the investigator's opinion
23. Corrected QT interval (\[QTc\] Fridericia) \> 480 ms
24. Significant vascular disease or recent peripheral arterial thrombosis
25. Subjects with active bleeding or pathologic conditions that carry high risk of bleeding
26. Subjects who are pregnant or lactating

Primary outcomes:
measure: Progression Free Survival
timeFrame: 12 Months
Secondary outcomes:
measure: Improvement in Objective Response Rate
timeFrame: 12 Months
measure: Overall Survival (OS)
timeFrame: 12 Months
measure: Proportion of Subjects Who Remain Progression-free at 12 Months
timeFrame: 12 Months
measure: Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability) of PCC Plus Bevacizumab and CA4P Versus PCC Plus Bevacizumab and Placebo
timeFrame: 12 Months
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: University of Alabama at Birmingham Comprehensive Cancer Center
state: Alabama
city: Mobile
country: United States
facility: Mitchell Cancer Institute - USA Health System
state: Alabama
city: Phoenix
country: United States
facility: Arizona Oncology Associates, PC - HAL
state: Arizona
city: Tucson
country: United States
facility: Arizona Oncology Associates, PC - HOPE
state: Arizona
city: Tucson
country: United States
facility: University of Arizona Cancer Center
state: Arizona
city: Lynwood
country: United States
facility: Oncology Institute of Hope and Innovation
state: California
city: Orange
country: United States
facility: University of California Irvine
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center, Research Institute
state: California
city: Santa Barbara
country: United States
facility: Sansum Clinic
state: California
city: Lakewood
country: United States
facility: Rocky Mountain Cancer Centers, LLP
state: Colorado
city: Hartford
country: United States
facility: Hartford Health Care Cancer Institute; Affiliate Memorial Sloan Kettering
state: Connecticut
city: Stamford
country: United States
facility: Stamford Hospital - Bennett Cancer Center
state: Connecticut
city: Miami
country: United States
facility: Sylvester Comprehensive Cancer Center University of Miami
state: Florida
city: Miami
country: United States
facility: Baptist Health Medical Group Oncology, LLC
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Augusta
country: United States
facility: Augusta University
state: Georgia
city: Scarborough
country: United States
facility: Maine Medical Center
state: Maine
city: Baltimore
country: United States
facility: Mercy Medical Center; The Institute for Cancer Care
state: Maryland
city: Kansas City
country: United States
facility: HCA Midwest Division - Sarah Cannon Cancer Institute
state: Missouri
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Canton
country: United States
facility: Gabrail Cancer Center
state: Ohio
city: Oklahoma City
country: United States
facility: Oklahoma Heath Sciences Center - Stephenson Cancer Center
state: Oklahoma
city: Tulsa
country: United States
facility: Tulsa Cancer Institute
state: Oklahoma
city: Portland
country: United States
facility: OHSU Center for Women's Health & Knight Cancer Institute
state: Oregon
city: Springfield
country: United States
facility: Willamette Valley Cancer Institute
state: Oregon
city: Allentown
country: United States
facility: Lehigh Valley Hospital, John and Dorothy Morgan Cancer Center; Affiliate Memorial Sloan Kettering
state: Pennsylvania
city: Pittsburgh
country: United States
facility: The Western Pennsylvania Hospital
state: Pennsylvania
city: Spartanburg
country: United States
facility: Gibbs Cancer Center & Research Institute Spartanburg Medical Center
state: South Carolina
city: Austin
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: Bedford
country: United States
facility: Texas Oncology
state: Texas
city: Dallas
country: United States
facility: Dallas County Hospital District d/b/a Parkland Health and Hospital System
state: Texas
city: Dallas
country: United States
facility: Simmons Comprehensive Cancer Center; UT Southwestern Medical Center
state: Texas
city: Dallas
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: San Antonio
country: United States
facility: Texas Oncology San Antonio
state: Texas
city: The Woodlands
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: Tyler
country: United States
facility: Texas Oncology, P.A.
state: Texas
city: Leuven
country: Belgium
facility: UZ Leuven
city: Erlangen
country: Germany
facility: Universitätsklinikum Erlangen
city: Essen
country: Germany
facility: Universitätsklinikum Essen (AöR) Klinik für Frauenheilkunde und Geburtshilfe
city: Tubingen
country: Germany
facility: Universitäts-Frauenklinik Dept. für Frauengesundheit
Study officials:
affiliation: Medical Monitor
name: Harish Dave, MD
role: STUDY_DIRECTOR
References: