Clinical trial NCT02584478: 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)
Official title: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE3
Conditions: Endometrial Carcinoma
Ovarian Carcinoma
Fallopian Tube Carcinoma
Primary Peritoneal Carcinoma
Cervical Carcinoma
Keywords: Dual receptor Tyrosine Kinase Inhibitor
Anti-angiogenic therapy
Combination Therapy
Lead sponsor: Advenchen Laboratories, LLC
Sponsor class: INDUSTRY
First posted: 2015-10-22
Enrollment: 294
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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).
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: Inclusion Critera

1. Female ≥ 18 years of age
2. 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:

1. Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3, platelets ≥ 100,000/mm3
2. 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.
3. Hepatic function: bilirubin ≤ 1.5 x ULN or ≤ 3.0 x ULN for subjects with Gilbert Syndrome; AST and ALT ≤ 3.0 × ULN.
4. Coagulation profile: international normalized ratio (INR) is ≤ 1.5 and an aPTT or PTT \< 1.2 x ULN
5. 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

1. Serious, non-healing wound, ulcer or bone fracture.
2. 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).
3. (Intentionally left blank)
4. Active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
5. 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.
6. 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.
7. 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.
8. Women who are pregnant or nursing.
9. (Intentionally left blank)
10. Clinically significant, uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
11. Hemoptysis within 3 months prior to enrollment.
12. Acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver dysfunction.
13. Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 28 days (42 days in cases of mitomycin C, nitrosourea, lomustine) prior to enrollment.
14. 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.
15. Known history of human immunodeficiency virus infection (HIV).
16. Active bacterial infections requiring systemic antibiotics (excluding uncomplicated urinary tract infection).
17. 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.
18. 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.
19. History of significant vascular disease (e.g. aortic aneurysm, aortic dissection).
20. Intra-abdominal abscess within the last 3 months of enrollment.
21. 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.
22. QTc \> 470 msec on screening ECG per Fridericia's formula.
23. History of or existing risk factors for Torsades de pointes (TdP) (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
24. Concurrent use of concomitant medications that prolong the QT/QTc interval.
25. Baseline echocardiogram (within 56 days of enrollment) with left ventricular ejection fraction (LVEF) \< 50%.
26. 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.
27. History of pancreatitis; history of renal disease that includes histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy or other renal insufficiencies.
28. Treatment with an investigational agent within 28 days of enrollment.
29. Known recreational substance abuse.
30. 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.
31. Known hypersensitivity to AL3818 or components of the formulation.

Primary outcomes:
measure: Recommended Phase 2 Dose (RP2D) - Part 1 (Phase 1b)
timeFrame: Cycle 1 (21-days)
measure: Objective Response Rates (ORR) - Part 2 (Phase 2a)
timeFrame: 12 months
measure: Measure the Progression Free Survival (PFS)- Part 3 ( Phase 3)
timeFrame: 12 Months
Secondary outcomes:
measure: 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)
timeFrame: Cycle 1 (Day 21)
measure: Clinical Benefit Rate (CBR) - Part 2 (Phase 2a)
timeFrame: 12 Months
measure: Progression-Free Survival (PFS) - Part 2 (Phase 2a)
timeFrame: Duration of time from the start of treatment to the time of documented disease progression or death, whichever comes first, followed for 12 months.
measure: Overall Survival (OS) - Part 2 (Phase 2a)
timeFrame: Cycle 1 Day 1 up to 5 years
measure: Objective Response Rate- Part 3 ( Phase 3)
timeFrame: 12 Months
measure: Duration Of Response - Part 3 ( Phase 3)
timeFrame: 12 Months
measure: Overall Survival - Part 3 ( Phase 3)
timeFrame: 12 Months
Other outcomes:
measure: Toxicity as assessed by CTCAE (v4.3) - Part 2 (Phase 2a)
timeFrame: 12 Months
Locations:
city: Long Beach
country: United States
facility: The Oncology Institute of Hope and Innovation
state: California
city: Miami
country: United States
facility: University of Miami Sylvester Comprehensive Cancer Center
state: Florida
city: Lexington
country: United States
facility: Baptist Health Lexington Oncology Research
state: Kentucky
city: Saint Louis
country: United States
facility: Washington University
state: Missouri
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: Pittsburgh
country: United States
facility: AHN West Penn Hospital
state: Pennsylvania
city: Dallas
country: United States
facility: UTSW
state: Texas
city: Madison
country: United States
facility: University of Wisconsin Madison
state: Wisconsin
city: Hefei
country: China
facility: Henan Cancer Hospital
state: Henan
city: Changchun
country: China
facility: Jilin Cancer Hospital
state: Jilin
city: Shenyang
country: China
facility: The First Hospital of China Medical University
state: Shenyang
city: Chongqing
country: China
facility: Zhongda Hospital Southeast University
state: Sichuan
city: Tianjin
country: China
facility: Tianjin Central Hospital of Gynecology Obstetrics
state: Tianjin
city: Shanghai
country: China
facility: Obstetrics&Gynecology Hospital of Fudan University
state: Yangpu District
city: Beijing
country: China
facility: Beijing Cancer Hospital
city: Chongqing
country: China
facility: Chongqing University Cancer Hospital
city: Weifang
country: China
facility: Weifang People's Hospital
city: Naples
country: Italy
facility: National Cancer Institute IRCCS "G. Pascale" Foundation
state: Campania
city: Bologna
country: Italy
facility: University Hospital of Bologna-IRCCS
state: Emilia-Romagna
city: Meldola (FC)
country: Italy
facility: Romagnolo Institute For the Study of Tumors "Dino Amadori"
state: Forlì-Cesena
city: Catania
country: Italy
facility: Cannizzaro Emergency Hospital
city: Milan
country: Italy
facility: Complex Structure Gynecology Oncology National Cancer Institute of Milan
city: Ravenna
country: Italy
facility: Operative Unit of Oncology
city: Rome
country: Italy
facility: Agostino Gemelli University Hospital Rome
city: Rome
country: Italy
facility: Campus Bio Medico University Hospital Foundation
city: Seoul,
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Samsung Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Córdoba
country: Spain
facility: Hospital Universitario Reina Sofía
state: Andalucía
city: Malaga
country: Spain
facility: Hospital Regional Universitario de Málaga
state: Andalucía
city: Badalona
country: Spain
facility: ICO Badalona
state: Catalunya
city: Barcelona
country: Spain
facility: Hospital Universitari Vall d'Hebrón
state: Catalunya
city: Valencia
country: Spain
facility: Hospital Clínico Universitario de Valencia
state: Comunidad Valenciana
city: Barcelona
country: Spain
facility: Hospital Clínic de Barcelona
city: Madrid
country: Spain
facility: Hospital Universitario Ramón y Cajal
city: Madrid
country: Spain
facility: Hospital Clínico San Carlos
city: Murcia
country: Spain
facility: HCU Virgen Arrixaca
city: Cambridge
country: United Kingdom
facility: Cambridge University Hospitals NHS Foundation Trust
state: Cambridgeshire
city: London
country: United Kingdom
facility: The Royal Marsden NHS Foundation Trust
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: Advenchen Laboratories, LLC
name: Clinical Director
role: STUDY_DIRECTOR
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