Evaluation of AL3818 in Combination With Nivolumab in Solid Tumors

This phase 1b/2 study evaluates the safety and efficacy of AL3818 (anlotinib) hydrochloride in combination with Opdivo (nivilumab) for the treatment patients with of metastatic, advanced, or recurrent solid tumors including soft tissue sarcomas (STS), non-small cell lung cancer (NSCLC), and small cell lung cancer (SCLC). All participants will receive open-label AL3818 with nivolumab on a scheduled basis.

Part 1 (phase 1b) consists of a dose finding phase to determine the safety, tolerability (including recommended phase 2 dosage (RP2D), and PK profile of AL3818 given with nivolumab. Participants will receive oral AL3818 once daily on Days 1-14 and nivolumab injection on Day 1 and 15 of one 21-day cycle.

Part 2 (phase 2a) consists of a dose expansion phase, to evaluate the safety and preliminary efficacy of combination treatment using AL3818 at the RP2D determined from Part 1 together with nivolumab injection at standard dosing for patients with metastatic, advanced, or recurrent STS, NSCLC, or SCLC in 21-day cycles. Oral AL3818 will be given on Days 1-14 days and nivolumab will be given every 2 weeks, for up to 24 cycles of total AL3818 therapy.

Key Inclusion Criteria:

• Part 1: Solid tumors of all histologies, including metastatic, locally advanced, or recurrent after at least one prior line of standard therapy and requiring further treatment; OR malignant tumors for which no standard therapy exists, with or without prior therapy.
• Part 2: Histologically confirmed soft tissue sarcomas (STS), small cell lung cancer (SCLC), and non-small cell lung cancer (NSCLC), after at least one prior line of standard therapy and requiring further treatment. For STS subtypes for which no standard therapy exists, patients without prior therapy may be included.
• Measurable disease by RECIST v1.1
• Disease progression or recurrence (after treatment) within 6 months prior to enrollment
• Last dose of prior anti-cancer therapy should be performed at least 21 days prior to the first administration of study treatment.
• Life expectancy of ≥ 3 months at the time of enrollment.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2
• Adequate baseline function within 28 days prior to enrollment:

• Bone marrow function: Absolute neutrophil count (ANC) ≥ 1,500/mm3; platelets ≥ 100,000/mm3 , Hemoglobin ≥ 9.0 g/dL.
• Renal function: Creatinine clearance (calculated by Cockcroft-Gault) must be ≥ 30 ml/min.
• Hepatic function: Bilirubin ≤ 1.5 x upper limit of normal (ULN) or ≤ 3.0 x ULN for subjects with Gilbert Syndrome; AST and ALT ≤ 3.0 × ULN.
• Coagulation profile: International normalized ratio (INR) is ≤ 2.0; absolute prothrombin time (aPTT) < 1.5 x ULN.
• Left ventricular ejection fraction (LVEF) of > 50% by ECHO or MUGA within 56 days prior to enrollment.
• Two blood pressure readings with systolic blood pressure < 140 mmHg and diastolic blood pressure < 90 mmHg at screening with 28 days prior to enrollment.
• Provide written informed consent before any study-specific procedures are initiated.

Key Exclusion Criteria:

• Major surgical procedure within 28 days or minor surgical procedure within 7 days prior to start of study treatment.
• History of prior or concurrent second primary malignancy that may interfere with the safety or efficacy assessment of the study treatment.
• Untreated, active central nervous system (CNS) metastases.
• Carcinomatous meningitis.
• Active, known, or suspected autoimmune disease or interstitial lung disease.
• Systemic treatment with corticosteroids or other immunosuppressive medications within 14 days prior to start of study treatment.
• Active peptic ulcer disease, inflammatory bowel disease, ulcerative colitis, or other gastrointestinal conditions with increased risk of perforation; history of abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within 28 days prior to start of study treatment.
• History of untreated deep venous thrombosis (DVT) within the past 6 months.
• Presence of uncontrolled infection.
• History of Class III or IV congestive heart failure according to New York Heart Association (NYHA) classification.
• History of any of the following cardiac conditions within 6 months prior to prior to start of study treatment:

• Cardiac angioplasty or stenting, or
• Myocardial infarction, or
• Unstable angina, or
• Cerebrovascular accident.
• Presence of any non-healing wound, fracture, or ulcer, or presence of symptomatic peripheral vascular disease.
• Evidence of bleeding diathesis or coagulopathy or clinically significant bleeding such as gross hematuria, gastrointestinal bleeding and hemoptysis within 6 months prior to start of study treatment.
• QTcF > 470 msec (per Fridericia's formula) on electrocardiogram within 28 prior to start of study treatment.
• Concurrent human Immunodeficiency virus (HIV) infection with CD4+ count < 350 cells/uL.
• Known history of acquired immunodeficiency syndrome (AIDS) and an opportunistic infection within the past 12 months.
• Serologic evidence of chronic hepatitis B virus (HBV) via positive hepatitis B virus surface antigen (HBVsAg) or hepatitis C virus ribonucleic acid (HCV antibody) with a viral load above the limit of quantification.
• History of hepatitis C virus (HCV) infection without completion of curative antiviral treatment with a viral load above the limit of quantification.
• History of organ transplantation.
• Clinical conditions affecting the intake or absorption of AL3818 (e.g., inability to swallow, chronic diarrhea, intestinal obstruction, malabsorption disease, stomach or small bowel resection).
• Known allergies, hypersensitivity, or intolerance to protein-based therapies or with a history of any significant drug allergy (e.g., anaphylaxis, hepatotoxicity, immune-mediated thrombocytopenia or anemia.