Phase 1/2a/3 Evaluation of Adding AL3818 to Standard Platinum-Based Chemotherapy in Subjects With Recurrent or Metastatic Endometrial, Ovarian, Fallopian, Primary Peritoneal or Cervical Carcinoma (AL3818-US-002)

Study Overview
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Brief Summary
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This trial is a Phase 1b/2a/3 trial designed to evaluate the safety and efficacy of adding oral AL3818 (Anlotinib, INN: Catequentinib), a Dual Receptor Tyrosine Kinase Inhibitor, to standard platinum-based chemotherapy concurrently in Subjects with Recurrent or Metastatic Endometrial, Ovarian, Fallopian, Primary Peritoneal or Cervical Carcinoma.

Detailed Description
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This trial is a Phase 1b/2a/3 trial designed to evaluate the safety and efficacy of adding oral AL3818(Anlotinib, INN: Catequentinib) to standard platinum-based chemotherapy concurrently and continued as a maintenance therapy for up to 12 months, in subjects with recurrent or metastatic endometrial, ovarian, fallopian, primary peritoneal, or cervical carcinoma. AL3818 is a novel small molecule dual receptor tyrosine kinase inhibitor, which shows highly selective inhibition of fibroblast growth factor receptor (FGFr) and vascular endothelial growth factor receptor (VEGFR). Preclinical studies of this agent in mouse models, including various cancer xenografts, have demonstrated that treatment of tumor-bearing mice with AL3818 induces tumor reductions. Phase 1 & 2: This study is divided into two parts. The objective of Part 1 is the evaluation of the safety and tolerability of adding oral AL3818 to standard carboplatin plus paclitaxel chemotherapy for a cycle of 21 days to determine the recommended Phase II dose (RP2D). Phase 1 / Part 1 is now complete. Part 2-The objective of Part 2 is evaluation of preliminary efficacy and the safety of adding oral AL3818 at the RP2D determined in Part 1 to carboplatin and paclitaxel chemotherapy for 6 cycles. Continuous maintenance mono therapy with 14 days on and 7 days off regimen at the RP2D will be conducted up to 12 months and is extendable beyond until disease progression. Phase I is closed and Phase 2 is closed. Phase 3: This study is currently a Phase III, multi-center, randomized trial with active control designed to evaluate the efficacy and safety of AL3818 8 mg plus background treatment (Active Arm) vs background treatment alone (Control Arm), where three background treatments, weekly paclitaxel, pegylated liposomal doxorubicin (PLD), and topotecan are utilized. Oral AL3818 8 mg may be given concurrently with background treatment or alone if the background treatment must be discontinued due to its toxicity for up to 24 cycles of therapy, in subjects with recurrent or metastatic platinum-resistant ovarian, fallopian tube, or primary peritoneal cancer. Phase 3 is open.

Official Title
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A Phase 1/2a/3 Evaluation of the Safety and Efficacy of Adding AL3818 (Anlotinib, INN: Catequentinib), a Dual Receptor Tyrosine Kinase Inhibitor, to Standard Platinum-Based Chemotherapy in Subjects With Recurrent or Metastatic Endometrial, Ovarian, Fallopian, Primary Peritoneal or Cervical Carcinoma

Conditions
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Endometrial Carcinoma, Ovarian Carcinoma, Fallopian Tube Carcinoma, Primary Peritoneal Carcinoma, Cervical Carcinoma

Intervention / Treatment
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* Drug: AL3818
* Drug: Paclitaxel
* Drug: Pegylated Liposomal Doxorubicin (PLD)
* Drug: Topotecan
* Drug: Topotecan
* Drug: Carboplatin
* Drug: Paclitaxel
* Drug: AL3818


Participation Criteria
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Eligibility Criteria
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Inclusion Critera Female ≥ 18 years of age Histologically proven diagnosis of: a. Endometrial and other uterine cancers with tumors of all histologies i. Recurrent Stage I to II endometrial and other uterine cancers, after at least one prior line of standard therapy, requiring further treatment with platinum-based chemotherapy ii. Advanced Stage III to IV endometrial and other uterine cancers requiring treatment with platinum-based chemotherapy b. Ovarian Cancer: Platinum-sensitive or platinum-resistant recurrent or metastatic ovarian, fallopian, or primary peritoneal cancer treated with at least one prior line of platinum-based chemotherapy and requiring further treatment.(Part 1/Phase Ib, Part 2/Phase 2a) Platinum-sensitive is defined as cancer progression ≥ 6 months after platinum- based chemotherapy. Platinum-resistant is defined as cancer progression < 6 months after platinum-based chemotherapy. Histologic cell types eligible are endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified. Phase III/Part 3: (1) Platinum-resistant (progression within 6 months after last platinum-based chemotherapy) ovarian, fallopian, or primary peritoneal cancer that meets one of the following criteria: i. Subject has received at least two prior lines of systemic therapy including a bevacizumab-containing regimen as standard of care ii. Subject has received at least two prior lines of systemic therapy, has not received a prior bevacizumab-containing regimen and is not eligible for a bevacizumab containing regimen based on Investigator's assessment (2) Platinum-refractory (progression during first-line platinum-based chemotherapy) ovarian, fallopian, or primary peritoneal cancer after at least one prior line of systemic therapy (3) For groups 1-2 above: Subjects with positive deleterious or suspected deleterious, germline or somatic BRCA mutated status must have received a PARP inhibitor as a prior line of therapy. c. Cervical cancer: recurrent or metastatic cervical cancer that is not amenable to curative treatment with surgery and/or radiation therapy after at least one prior line of standard therapy, requiring further treatment. Histologic cell types eligible are squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma 3. Have measureable disease defined by RECIST 1.1 confirmed by CT or MRI scan within 28 days of enrollment. 4. Life expectancy of ≥ 3 months at the time of enrollment. 5. Able to take orally administered study medication. 6. Have adequate baseline function and performance status within 28 days of enrollment: Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3, platelets ≥ 100,000/mm3 Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN) or if creatinine is > 1.5 x ULN, creatinine clearance must be > 50 mL/min. Hepatic function: bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN for subjects with Gilbert Syndrome; AST and ALT ≤ 3.0 × ULN. Coagulation profile: international normalized ratio (INR) is ≤ 1.5 and an aPTT or PTT < 1.2 x ULN ECOG performance ≤ 2 7. Women of child-bearing potential must agree to use contraceptive measures starting 1 week before C1D1 until 4 weeks after the last dose of study treatment and have a negative serum pregnancy test within 28 days of enrollment. 8. Provide written informed consent and authorization permitting release of Protected Health Information. 9. Ability and willingness to comply with the study protocol for the duration of the study and with follow-up procedures. Exclusion Criteria Serious, non-healing wound, ulcer or bone fracture. Major surgical procedure within 28 days or minor surgical procedure performed within 7 days prior to C1D1 (a major surgical procedure is defined as requiring general anesthesia). (Intentionally left blank) Active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels. History or evidence upon physical examination of central nervous system (CNS) disease including primary brain tumor; seizures not controlled with standard medical therapy; and history of cerebrovascular accident (CVA, stroke), transient ischemic attack (TIA), or subarachnoid hemorrhage within 6 months of enrollment. a. Subjects with metastatic CNS tumors may participate in this study if the subject is > 28 days from therapy completion (including radiation and/or surgery), is clinically stable at the time of study enrollment, and is not receiving corticosteroid therapy. Proteinuria on urinalysis within 28 days of enrollment. Subjects discovered to have a urine protein of 1+ on dipstick or ≥ 30 mg/dl at baseline should undergo a 24-hour urine collection and demonstrate < 1000 mg protein per 24 hours or spot urine protein (mg/dL) to creatinine (mg/dL) ratio must be <1.0 to allow participation in the study. Clinically significant cardiovascular disease including uncontrolled hypertension; myocardial infarction or unstable angina within 6 months prior to enrollment; New York Heart Association (NYHA) Grade II or greater congestive heart failure (Appendix E); serious cardiac arrhythmia requiring medication; and Grade II or greater peripheral vascular disease. Women who are pregnant or nursing. (Intentionally left blank) Clinically significant, uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia. Hemoptysis within 3 months prior to enrollment. Acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver dysfunction. Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 28 days (42 days in cases of mitomycin C, nitrosourea, lomustine) prior to enrollment. Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 within 14 days prior to enrollment and during the study unless there is an emergent or life-threatening medical condition that required it. Known history of human immunodeficiency virus infection (HIV). Active bacterial infections requiring systemic antibiotics (excluding uncomplicated urinary tract infection). Other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of other cancer present within the last 5 years prior to enrollment or whose previous cancer treatment contraindicates this protocol therapy. History of non-malignant gastrointestinal bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3-months prior to enrollment that in the opinion of the investigator may place the subject at risk of side effects on an anti-angiogenesis product. History of significant vascular disease (e.g. aortic aneurysm, aortic dissection). Intra-abdominal abscess within the last 3 months of enrollment. Pre-existing uncontrolled hypertension as documented by two baseline blood pressure readings taken at least five minutes apart, defined as systolic BP >160 mm Hg or diastolic BP > 90 mm Hg pressure. QTc > 470 msec on screening ECG per Fridericia's formula. History of or existing risk factors for Torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome). Concurrent use of concomitant medications that prolong the QT/QTc interval. Baseline echocardiogram (within 56 days of enrollment) with left ventricular ejection fraction (LVEF) < 50%. History of difficulty swallowing, malabsorption, active partial or complete bowel obstruction, or other chronic gastrointestinal disease or condition that may hamper compliance and/or absorption of AL3818. History of pancreatitis; history of renal disease that includes histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy or other renal insufficiencies. Treatment with an investigational agent within 28 days of enrollment. Known recreational substance abuse. Anticoagulation therapy with warfarin. Subjects treated with heparin, low molecular weight heparin, or any other anticoagulant may be included provided the subject has been on a stable therapeutic dose of the anticoagulant for at least 14 days prior to enrollment. Known hypersensitivity to AL3818 or components of the formulation.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Overall duration of the study will be approximately 42 months. Part 1 and 2 of this study are not randomized and have no concurrent controls. AL3818 and chemotherapy will be administered in an open-label fashion. Phase III/Part 3 is unblinded and randomized. Within each one of the three background chemotherapy groups, subjects will be randomized at a 1:1 ratio stratified by prior angiogenesis inhibitors mainly Avastin use status (Yes or No) and number of prior treatment (≤3 or >3) to receive AL3818 plus background chemotherapy (Active Arm) or background chemotherapy alone (Control Arm).
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 3 -Active Treatment Arm<br>Phase 3: AL3818 8 mg once daily in combination with one background chemotherapy in 21-day cycles. Platinum resistant recurrent or metastatic ovarian, fallopian, or primary peritoneal cancer subjects will be enrolled into one of the following three background chemotherapy groups: Weekly paclitaxel (default choice; if the subject is ineligible for paclitaxel, the investigator will select from PLD or topotecan) Pegylated liposomal doxorubicin (PLD) Topotecan | Drug: AL3818<br>* Taken daily from Day 8 to Day 21 (14 days),administered orally combination with one background chemotherapy in 21-day cycles.<br>* Other names: Catequentinib;Drug: Paclitaxel<br>* Weekly single agent Paclitaxel will be administered on Day 1, 8, and 15 of each 21-day cycle. Suggested dose: 80 mg/m^2 intravenously or local standard. Paclitaxel may also be administered once weekly with a 1-week break every 3 weeks in lieu of every week<br>Drug: Pegylated Liposomal Doxorubicin (PLD)<br>* Single agent Pegylated Liposomal Doxorubicin (PLD) administered every 4 weeks on the following cycle days corresponding with AL3818 cycles until maximum cumulative dose per local standard reached. Suggested dose: 40 mg/m^2 intravenously or local standard<br>Drug: Topotecan<br>* Daily Topotecan on Days 1-5 of each 21-day cycle Suggested dose: 1.25 mg/m2 intravenously or local standard OR Weekly Topotecan with a 1 week break every 3 weeks. Suggested dose: 4 mg/m2 intravenously or local standard<br>* Other names: Daily Topotecan;Drug: Topotecan<br>* Weekly Topotecan with a 1 week break every 3 weeks Suggested dose: 4 mg/m2 intravenously or local standard<br>* Other names: Weekly Topotecan;|
| Other: Phase 3-Control Treatment Arm<br>Control Treatment Arm: Background chemotherapy treatment alone. Platinum resistant recurrent or metastatic ovarian, fallopian, or primary peritoneal cancer subjects will be enrolled into one of the following three background chemotherapy groups: Weekly paclitaxel (default choice; if the subject is ineligible for paclitaxel, the investigator will select from PLD or topotecan) Pegylated liposomal doxorubicin (PLD) Topotecan | Drug: Paclitaxel<br>* Weekly single agent Paclitaxel will be administered on Day 1, 8, and 15 of each 21-day cycle. Suggested dose: 80 mg/m^2 intravenously or local standard. Paclitaxel may also be administered once weekly with a 1-week break every 3 weeks in lieu of every week<br>Drug: Pegylated Liposomal Doxorubicin (PLD)<br>* Single agent Pegylated Liposomal Doxorubicin (PLD) administered every 4 weeks on the following cycle days corresponding with AL3818 cycles until maximum cumulative dose per local standard reached. Suggested dose: 40 mg/m^2 intravenously or local standard<br>Drug: Topotecan<br>* Daily Topotecan on Days 1-5 of each 21-day cycle Suggested dose: 1.25 mg/m2 intravenously or local standard OR Weekly Topotecan with a 1 week break every 3 weeks. Suggested dose: 4 mg/m2 intravenously or local standard<br>* Other names: Daily Topotecan;Drug: Topotecan<br>* Weekly Topotecan with a 1 week break every 3 weeks Suggested dose: 4 mg/m2 intravenously or local standard<br>* Other names: Weekly Topotecan;|
| Experimental: Phase 1b: AL3818 plus carboplatin and paclitaxel<br>Phase 1b: Sequential deescalating dosing evaluation to determine the recommended Phase II dose (RP2D). For 21-day treatment cycles, cohort 1 (3 subjects) will be administered carboplatin (AUC 5/6 over 30 minutes) and paclitaxel (175mg/m2 over 3 hours) intravenously on Day 1. AL3818 is orally administered daily starting on Day 8 until Day 21 (14 days) at an initial dose of 12 mg/day. | Drug: Carboplatin<br>* AUC 5/6 on Day 1 of each 21-Day cycles<br>* Other names: Paraplatin;Drug: Paclitaxel<br>* 175mg/m2 IV over 3 hours on Day 1 of each 21-Day cycle<br>* Other names: Taxol;Drug: AL3818<br>* Taken daily from Day 8 to Day 21 (14 days). Administered orally.<br>|
| Experimental: Phase 2a: AL3818 plus carboplatin and paclitaxel<br>Phase 2a: subjects will receive chemotherapy and oral AL3818 for 6 cycles (18 weeks, 21-day cycles of treatment) followed by continuous maintenance treatment of oral AL3818 for up to 12 months. Subjects will be administered carboplatin (AUC 5/6 over 30 minutes) and paclitaxel (175mg/m2 over 3 hours) intravenously on Day 1. AL3818 is orally administered daily starting on Day 8 until Day 21 (14 days) at the RP2D found in Phase 1b. | Drug: Carboplatin<br>* AUC 5/6 on Day 1 of each 21-Day cycles<br>* Other names: Paraplatin;Drug: Paclitaxel<br>* 175mg/m2 IV over 3 hours on Day 1 of each 21-Day cycle<br>* Other names: Taxol;Drug: AL3818<br>* Taken daily from Day 8 to Day 21 (14 days). Administered orally.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose (RP2D) - Part 1 (Phase 1b) | Determine the Recommended Phase 2 Dose (RP2D) via evaluation of dose limiting toxicity (DLT) events. | Cycle 1 (21-days) | 
| Objective Response Rates (ORR) - Part 2 (Phase 2a) | Evaluated by Response Evaluation Criteria In Solid Tumors (RECIST, v1.1) criteria after three complete 21-day cycles in the first 9 cycles then once every 6 cycles for up to 12 months. ORR is measured by the number of complete (CR) and partial responses (PR) | 12 months | 
| Measure the Progression Free Survival (PFS)- Part 3 ( Phase 3) | To evaluate the efficacy between the Active Arm (AL3818 in combination with background chemotherapy) and Control Arm (background chemotherapy alone arm) as measured by the primary endpoint of Progression Free Survival (PFS). | 12 Months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants with Adverse Events as a measure of safety and toxicity of 21-Day cycles of AL3818 as measured by incidence and severity of treatment-related adverse events (TRAE) - Part 1 (Phase 1b) | Incidence and severity of treatment-related adverse events reported and their relationship to AL3818 will be assessed by the Common Terminology Criteria for Adverse Events (CTCAE v4.3). | Cycle 1 (Day 21) | 
| Clinical Benefit Rate (CBR) - Part 2 (Phase 2a) | Evaluated by Response Evaluation Criteria In Solid Tumors (RECIST, v1.1) criteria after three complete 21-day cycles in the first 9 cycles then once every 6 cycles for up to 12 months. Measured as CR+PR+SD (SD ≥ 16 weeks from inclusion). | 12 Months | 
| Progression-Free Survival (PFS) - Part 2 (Phase 2a) | Evaluated by Response Evaluation Criteria In Solid Tumors (RECIST, v1.1) criteria after three complete 21-day cycles in the first 9 cycles then once every 6 cycles for up to 12 months. Kaplan-Meier analysis | Duration of time from the start of treatment to the time of documented disease progression or death, whichever comes first, followed for 12 months. | 
| Overall Survival (OS) - Part 2 (Phase 2a) | Overall survival is defined as the date the study treatment was initiated to the date of death from any cause. Kaplan-Meier analysis | Cycle 1 Day 1 up to 5 years | 
| Objective Response Rate- Part 3 ( Phase 3) | To evaluate the efficacy between the Active Arm and Control Arm as measured by the secondary endpoints of objective response rate (ORR). (OS). | 12 Months | 
| Duration Of Response - Part 3 ( Phase 3) | To evaluate the efficacy between the Active Arm and Control Arm as measured by the secondary endpoints of duration of response (DOR) | 12 Months | 
| Overall Survival - Part 3 ( Phase 3) | To evaluate the efficacy between the Active Arm and Control Arm as measured by the endpoints of Overall survival | 12 Months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Dual receptor Tyrosine Kinase Inhibitor, Anti-angiogenic therapy, Combination Therapy