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Phase 1/2a 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) (AL3818)

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ClinicalTrials.gov Identifier: NCT02584478
Recruitment Status : Recruiting
First Posted : October 22, 2015
Last Update Posted : June 18, 2019
Sponsor:
Information provided by (Responsible Party):
Advenchen Laboratories, LLC

Brief Summary:
This trial is a Phase 1b/2a trial designed to evaluate the safety and efficacy of adding oral AL3818 to standard platinum-based chemotherapy concurrently and continued as a maintenance therapy for up to 12 months.

Condition or disease Intervention/treatment Phase
Endometrial Carcinoma Ovarian Carcinoma Fallopian Tube Carcinoma Primary Peritoneal Carcinoma Cervical Carcinoma Drug: AL3818 Drug: Carboplatin Drug: Paclitaxel Phase 1 Phase 2

Detailed Description:

This trial is a Phase 1b/2a trial designed to evaluate the safety and efficacy of adding oral AL3818 to standard platinum-based chemotherapy such as carboplatin plus paclitaxel, 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.

This study will be 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). 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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 48 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/2a Evaluation of the Safety and Efficacy of Adding AL3818, 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 (AL3818-US-002)
Study Start Date : December 2015
Estimated Primary Completion Date : December 2020
Estimated Study Completion Date : December 2020


Arm Intervention/treatment
Experimental: AL3818 plus carboplatin and paclitaxel

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.

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: AL3818
Taken daily from Day 8 to Day 21 (14 days). Administered orally.
Other Name: Anlotinib Hydrochloride

Drug: Carboplatin
AUC 5/6 on Day 1 of each 21-Day cycles
Other Name: Paraplatin

Drug: Paclitaxel
175mg/m2 IV over 3 hours on Day 1 of each 21-Day cycle
Other Name: Taxol




Primary Outcome Measures :
  1. Recommended Phase 2 Dose (RP2D) - Part 1 (Phase 1b) [ Time Frame: Cycle 1 (21-days) ]
    Determine the Recommended Phase 2 Dose (RP2D) via evaluation of dose limiting toxicity (DLT) events.

  2. Objective Response Rates (ORR) - Part 2 (Phase 2a) [ Time Frame: 12 months ]
    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)


Secondary Outcome Measures :
  1. 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) [ Time Frame: Cycle 1 (Day 21) ]
    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).

  2. Clinical Benefit Rate (CBR) - Part 2 (Phase 2a) [ Time Frame: 12 Months ]
    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).

  3. Progression-Free Survival (PFS) - Part 2 (Phase 2a) [ Time Frame: Duration of time from the start of treatment to the time of documented disease progression or death, whichever comes first, followed for 12 months. ]
    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

  4. Overall Survival (OS) - Part 2 (Phase 2a) [ Time Frame: Cycle 1 Day 1 up to 5 years ]
    Overall survival is defined as the date the study treatment was initiated to the date of death from any cause. Kaplan-Meier analysis


Other Outcome Measures:
  1. Toxicity as assessed by CTCAE (v4.3) - Part 2 (Phase 2a) [ Time Frame: 12 Months ]
    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)



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
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.

    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. c. Cervical cancer: recurrent or metastatic cervical cancer that is not amenable to curative treatment with surgery and/or radiation therapy and has not been previously treated with chemotherapy for recurrence.

    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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02584478


Contacts
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Contact: Judy Chen, Pharm.D. 805-530-1550 judyc@advenchen.com

Locations
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United States, California
The Oncology Institute of Hope and Innovation Recruiting
Long Beach, California, United States, 90805
Contact: Rosely Study Coordinator       rjimenez@icrinstitute.com   
Principal Investigator: Eric M Cheung, DO         
United States, Florida
University of Miami Sylvester Comprehensive Cancer Center Recruiting
Miami, Florida, United States, 33136
Contact: Negin Study Coordinator       negin.khameneh@med.miami.edu   
Principal Investigator: Marilyn Huang, MD         
United States, Louisiana
LSU Health New Orleans Recruiting
New Orleans, Louisiana, United States, 70112
Contact: Melissa Study Coordinator       Melissa.Forschler@lcmchealth.org   
Principal Investigator: Agustin Garcia, MD         
United States, Texas
UTSW Recruiting
Dallas, Texas, United States, 75390
Contact: Isabel Study Coordinator       Isabel.Villalobos@utsouthwestern.edu   
Principal Investigator: David Miler, MD         
Sponsors and Collaborators
Advenchen Laboratories, LLC
Investigators
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Study Director: Clinical Director Advenchen Laboratories, LLC

Additional Information:
Publications:
Ledermann JA, Perren TJ, Raja FA, et al: Randomized double-blind phase III trial of cediranib (AZD 2171) in relapsed platinum-sensitive ovarian cancer: Results of the ICON6 trial. European Cancer Congress. Abstract 10. Presented September 30, 2013.
Burger RA, Brady MF, Bookman MA et al. Phase III trial of bevacizumab (BEV) in the primary treatment of advanced epithelial ovarian cancer (EOC), primary peritoneal cancer (PPC) or fallopian tube cancer (FTC): A Gynecologic Oncology Group study. Journal of Clinical Oncology, 2010 ASCO Annual Meeting Proceedings. Vol. 28, No 18S, 2010 June 20 suppl: Abstract LBA1
Cella DF. Manual for the Functional Assessment of Cancer Therapy (FACT) Measurement System (version 4). Center for Outcomes, Research and Education (CORE), Northwestern University, Chicago, 1997
36. Krishnansu Sujata Tewari, Michael Sill, Harry J. Long,et al. Plenary Session, Abstract # 3, J Clin Oncol 31, 2013 (suppl; abstract 3)

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Responsible Party: Advenchen Laboratories, LLC
ClinicalTrials.gov Identifier: NCT02584478     History of Changes
Other Study ID Numbers: AL3818-US-002
First Posted: October 22, 2015    Key Record Dates
Last Update Posted: June 18, 2019
Last Verified: June 2019
Keywords provided by Advenchen Laboratories, LLC:
Dual receptor Tyrosine Kinase Inhibitor
Anti-angiogenic therapy
Combination Therapy
Additional relevant MeSH terms:
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Carcinoma
Endometrial Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Uterine Neoplasms
Genital Neoplasms, Female
Urogenital Neoplasms
Neoplasms by Site
Uterine Diseases
Genital Diseases, Female
Paclitaxel
Albumin-Bound Paclitaxel
Carboplatin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action