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)

Study ID
STU 042017-051

Study Sites

  • Clements University Hospital

Contact
Isabel Villalobos
214/648-7010
isabel.villalobos@utsouthwestern.edu

Principal Investigator
David Miller, M.D.

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)

Brief Overview

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.

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.

Eligibility

Inclusion Criteria:
- Female ≥ 18 years
- Previously histologically proven diagnosis of
a. Endometrial Cancer: recurrent or persistent endometrial carcinoma refractory to conventional therapy or established treatments with the following histologic epithelial cell types i. Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified, mucinous adenocarcinoma, squamous cell carcinoma, and transitional cell carcinoma b. Ovarian Cancer: recurrent or persistent ovarian or primary peritoneal cancer refractory to established treatments with the following histologic epithelial cell types i. Endometrioid adenocarcinoma, serous adenocarcinoma, undifferentiated carcinoma, clear cell adenocarcinoma, mixed epithelial carcinoma, adenocarcinoma not otherwise specified.
c. Cervical cancer: squamous cell carcinoma of the cervix refractory to conventional therapy or established treatments with the following histologic epithelial cell types: i. Squamous cell carcinoma, adenosquamous carcinoma or adenocarcinoma Measurable disease defined as at least one lesion that can be accurately measured in at least one dimension (longest dimension to be recorded). Each lesion must be ≥ 20mm when measured by conventional techniques, including palpation, plain x-ray, CT, and MRI or ≥ 10mm when measured by spiral CT.
- Life expectancy ≥ 3 months
- Able to take orally administered study medication
- Must sign approved informed consent and authorization permitting release of personal health information.
- Patient must have adequate:
1. Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm^3, equivalent to Common Toxicity Criteria (CTC) grade 1, platelets ≥ 100,000/mm^3
2. Renal function: creatinine ≤ 1.5 x institutional upper limit normal (ULN), CTC grade 1. Note: If creatinine is > 1.5 x ULN, creatinine clearance must be > 50 mL/min.
3. Hepatic function: bilirubin ≤ 1.5 x ULN (CTC grade 1) or ≤ 3.0 x ULN for subjects with Gilbert Syndrome; AST and ALT ≤ 3.0 ×ULN.
4. Coagulation profile: PT such that international normalized ratio (INR) is ≤ 1.55 (or an in-range INR, usually between 2 and 3, if a patient is on a stable dose of therapeutic warfarin or low molecular weight heparin) and a PTT < 1.2 times control.
5. ECOG performance ≤ 2
- Patient of child-bearing potential must agree to use contraceptive measures starting 1 week before the administration of the first dose of AL3818 until 4 weeks after discontinuing study drug and have a negative serum pregnancy test prior to study entry and cannot be lactating.
- Ability and willingness to comply with the study protocol for the duration of the study and with follow-up procedures.
Exclusion Criteria:
- Patients with serious, non-healing wound, ulcer or bone fracture.
- Patients with active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
- Patient with history or evidence upon physical examination of CNS disease, including primary brain tumor, seizures not controlled with standard medical therapy, any brain metastases or history of cerebrovascular accident (CVA, stroke) transient ischemic attack (TIA) or subarachnoid hemorrhage within 6 months of the first date of treatment on this study.
a. Patients with metastatic CNS tumors may participate in this trial, if the patient is > 4 weeks from therapy completion (including radiation and/or surgery), is clinically stable at the time of study entry and is not receiving corticosteroid therapy.
- Patients with proteinuria: patients discovered to have a urine protein of 1+ on dipstick or ≥ 30 mg/dl at baseline should undergo a 24-hour urine collection, which must be an adequate collection and must demonstrate < 1000 mg protein/24 hours to allow participation in the study.
- Patients with clinically significant cardiovascular disease including uncontrolled hypertension, myocardial infarction or unstable angina within 6 months prior to registration. New York Heart Association (NYHA) Grade II or greater congestive heart failure, Serious cardiac arrhythmia requiring medication, Grade II or greater peripheral vascular disease.
- Patients who are pregnant or nursing.
- Women of childbearing potential who are unable to use contraceptive measures during study therapy and for at least 3 months after completion of AL3818 therapy.
- Patients with uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
- Hemoptysis within 3 months prior to first scheduled dose of AL3818.
- Patients with acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver dysfunction.
- Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 4 weeks (6 weeks in cases of mitomycin C, nitrosourea, lomustine) prior to first scheduled dose of AL3818 or a major surgical procedure within 28 days or minor surgical procedure performed within 7 days prior to first scheduled dose of AL3818.
- Concomitant treatment with strong inhibitors or inducers of CYP3A4, CYP2C9 and CYP2C19 who cannot be switched to other alternative medications .
- Known history of human immunodeficiency virus infection (HIV).
- Subjects with active bacterial infections (other than uncomplicated urinary tract infection) and/or receiving systemic antibiotics.
- Patients with 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 or whose previous cancer treatment contraindicates this protocol therapy.
- History of non-malignant GI bleeding, gastric stress ulcerations, or peptic ulcer disease within the past 3-months that in the opinion of the investigator may place the patient 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.
- Pre-existing uncontrolled hypertension as documented by 2 baseline BP readings taken at least one hour apart, defined as systolic bloodpressure (BP) >160 mm Hg or diastolic BP > 90 mm Hg pressure.
- QTcF>470 msec on screening ECG.
- A history of additional risk factors for TdP (e.g., heart failure, hypokalemia, family history of Long QT Syndrome).
- The use of concomitant medications that prolong the QT/QTc interval. Baseline echocardiogram (within 2 months) 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 and/or renal disease or pancreatitis that includes histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy, or other renal insufficiencies.
- Treatment with an investigational agent within the longest time frame of either 5 half- lives or 30 days of initiating study drug.
- Known recreational substance abuse.
- Known hypersensitivity to AL3818 or components of the formulation.