A Study of Catequentinib Hydrochloride (AL3818) in Endometrial, LGSOC, STS or GBM Cancers

AL-GB-900 is an international, multicenter, open-label, nonrandomized phase 1b/2a study of oral AL3818, a fibroblast growth factor receptor and vascular endothelial growth factor receptor tyrosine kinase inhibitor. AL3818 is evaluated as monotherapy and in combination with oral AL58805, a PI3K/mTOR inhibitor, or with the alkylating agents temozolomide or lomustine.

Phase 1b uses protocol-defined 3+3 dose-exploration cohorts to select a monotherapy recommended phase 2 dose (RP2D) and regimen-specific recommended combination doses (RCDs) based on dose-limiting toxicities (DLTs) during the first cycle. Cohort A1 evaluates AL3818 monotherapy in adults with recurrent or metastatic non-small cell lung cancer, small cell lung cancer, soft tissue sarcoma, thyroid cancer, endometrial cancer, low-grade serous ovarian cancer, or breast cancer. Cohort A2 evaluates AL3818 plus AL58805 in endometrial cancer, low-grade serous ovarian cancer, or soft tissue sarcoma. Cohort B1 evaluates an AL3818 monotherapy run-in in glioblastoma, and eligible participants may transition to Cohort B2 for separate dose evaluations of AL3818 plus temozolomide or AL3818 plus lomustine.

Phase 2a evaluates preliminary efficacy and further safety at the selected doses. Cohort C evaluates AL3818 monotherapy in separate endometrial cancer molecular groups (TP53-mutated adenocarcinoma, TP53-associated carcinosarcoma, and TP53-wild-type disease) and in low-grade serous ovarian cancer. Cohort D evaluates AL3818 plus AL58805 in separate endometrial cancer, low-grade serous ovarian cancer, and soft tissue sarcoma groups. Cohort E evaluates AL3818 plus temozolomide and AL3818 plus lomustine in separate glioblastoma groups.

For non-glioblastoma phase 2a groups, the primary activity measure is objective response rate according to RECIST version 1.1. For glioblastoma, the primary activity measure is the proportion of participants alive and progression-free at 6 months according to RECIST version 1.1. Imaging is generally performed at baseline and approximately every 8 weeks. Complete or partial responses are confirmed by repeat imaging 4 to 8 weeks later.

Study treatment may continue for up to 12 months or until disease progression, unacceptable toxicity, withdrawal, intercurrent illness, or sponsor termination. Temozolomide or lomustine is administered for no more than 6 cycles; participants may continue AL3818 afterward if otherwise eligible. Participants who remain without progression and continue to benefit may continue protocol-specified compassionate-care treatment beyond 12 months at the investigator's discretion. The sponsor must reconcile the enrollment arithmetic, the glioblastoma statistical decision rule, and several dose specifications before the record is released.

Inclusion criteria

• Subjects must meet all of the following inclusion criteria to be eligible for this study:

• Age ≥ 18 years.
• Histologically proven diagnosis of:

• Pathologically confirmed recurrent or metastatic solid tumors such as NSCLC, SCLC, STS, Thyroid, Endometrial, LGSOC, GBM and breast cancer (Phase 2a: STS, Endometrial, LGSOC and GBM ); GBM can only have histological confirmation of diagnosis;
• Failure of at least 1 prior line of standard therapy (disease progression after treatment or intolerable treatment toxicities); concurrent chemoradiation therapy and adjuvant chemotherapy such as containing temozolomide will be considered as 1 line of prior therapy
• no standard or effective treatment available.
• Measurable disease is not required in phase 1b. Have measurable disease defined by RECIST 1.1 (or RANO 2.0 for GBM by MRI) confirmed by CT or MRI scan within 28 days of enrollment in phase 2a.
• Life expectancy of ≥ 3 months at the time of enrollment.
• Able to take orally administered study medication.
• Have adequate baseline function and performance status within 28 days of enrollment:

• Bone marrow function: absolute neutrophil count (ANC) ≥ 1,500/mm3, platelets ≥75,000/mm3 and Hemoglobin ≥ 9g/dl.
• 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; No liver metastasis, AST and ALT ≤ 2.5 × ULN; When liver metastasis occurs, AST and ALT ≤ 5.0 × ULN.
• Coagulation profile: international normalized ratio (INR) is ≤ 1.5 and an aPTT or PTT < 1.2 x ULN.
• ECOG performance ≤ 2
• Left ventricular ejection fraction (LVEF) ≥ 50%
• No gastrointestinal diseases that affect drug absorption, such as malabsorption.
• 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. The patient must be non-lactating; if a female patient has not yet reached menopause (menopause is defined as the cessation of menstruation for at least 12 consecutive months, with no other causes), and has not undergone sterilization (removal of the ovaries and/or uterus), she is considered to be fertile. Her sexual partner should use medically approved contraception during the treatment period and for 4 weeks after the treatment ends;
• Provide written informed consent and authorization permitting release of Protected Health Information.
• Ability and willingness to comply with the study protocol for the duration of the study and with follow-up procedures.
• For GBM patients only:

• Prior therapy with gamma knife or other focal high-dose radiation is allowed, but at least 2 weeks (14 days) must have elapsed from the time of treatment, and the patient must have subsequent histologic documentation of recurrence, unless the recurrence is a new lesion outside the irradiated field.
• Prior therapy with Laser Induced Thermal Therapy (LITT) is allowed, but at least 21 days must have elapsed from last LITT, with recovery from all LITT-related toxicities to Grade 1 or less and subsequent histologic documentation of recurrence.
• For those patients using the Optune™ device, it will be discontinued at least 14 days before initiating treatment with either study medication, the patient must have recovered from all treatment-related toxicities to Grade 1 or less.
• Patients must have a Karnofsky performance scale score ≥ 60.
• Maximum dexamethasone dose (or equivalent dose) of 2 mg daily.
• The contrast enhancing portion of the tumors must be ≥1.0 cm in diameter.

Exclusion criteria

• Subjects presenting with any of the following will not be included in the study:

• Treatment with an investigational agent within 28 days of enrollment.
• Cytotoxic chemotherapy, targeted therapies, immunotherapy, or radiotherapy within 28 days (42 days in cases of mitomycin C, nitrosourea, lomustine) prior to enrollment. Prior bevacizumab or other antiangiogenic therapies for phase 2 part of the GBM cohort (however, use of bevacizumab for radiation necrosis or toxicity is allowed unless it is within 28 days 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 allergy or intolerance to investigational drugs (e.g., AL3818, AL58805, temozolomide, CCNU, etc.) and excipients. (For example, patients who have had severe allergic reactions such as rash or anaphylactic shock after previous use of temozolomide.)
• Other invasive malignancies, with the exception of non-melanoma skin cancer, who had (or have) any evidence of other cancer presents within the last 5 years prior to enrollment or whose previous cancer treatment contraindicates this protocol therapy.
• Myocardial infarction or unstable angina within 6 months prior to enrollment; New York Heart Association (NYHA) Grade II or greater congestive heart failure; serious cardiac arrhythmia requiring medication; and Grade II or greater peripheral vascular disease.
• Pre-existing uncontrolled hypertension as documented by two baseline blood pressure readings taken at least five minutes apart, defined as systolic BP >150 mm Hg or diastolic BP>90 mm Hg pressure.
• QTc ≥ 480 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.
• History of significant vascular disease (e.g. aortic aneurysm, aortic dissection, peripheral vascular disease).
• Patients with severe chronic obstructive pulmonary disease (COPD) in acute exacerbation, severe pulmonary fibrosis (such as idiopathic pulmonary fibrosis with rapid disease progression), etc.
• History or evidence upon physical examination of central nervous system (CNS) disease including primary brain tumor (not applicable for GBM cohorts); 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.

• History of neurological or psychiatric disorder, such as dementia, mood disorder, etc. which in the investigator's assessment may prevent protocol compliance such as inability of ICF execution.
• 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).
• Diabetes with poor blood sugar control. (If a patient with diabetes requires long-term use of insulin or hypoglycemic drugs, with no history of hypoglycemic drug dose adjustment in the past 1 month, they may be considered for inclusion after investigator assessment, even if their HbA1c is between 7.5% and 8.0%.)
• History of pancreatitis; history of renal disease that includes histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy or other renal insufficiencies.
• 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, uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcaemia.
• Hemoptysis within 3 months prior to enrollment.
• Acute or chronic liver disease, active hepatitis A, B, or C with known cirrhosis or liver dysfunction.
• Active bacterial infections requiring IV antibiotics (excluding uncomplicated urinary tract infection).
• Active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels.
• 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.
• Intra-abdominal abscess within the last 3 months of enrollment.
• Ascites or pleural effusion (CTCAE5.0≥2)
• 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.
• 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 history of human immunodeficiency virus infection (HIV) with viral load is detectable.
• HBsAg-positive patients with HBV DNA ≥ 104 copies or ≥ 2000IU/mL, antiviral and liver protection treatment should be performed first, and they can be enrolled only when HBV-DNA ≤ 104 copies/mL (2000IU/mL), and continue to take antiviral drugs, monitor liver function and hepatitis B virus load; HCV antibody positive and HCV-RNA positive.
• The investigator deems that the subject is not suitable to participate in this study.
• For GBM patients only:

• Prior treatment with cranial/brain radiation precluding standard of care chemoradiation therapy with concurrent temozolomide for 6 weeks.
• Leptomeningeal disease, infratentorial disease, spinal cord disease.
• Less than 12 weeks from completion of standard chemoradiation with concurrent temozolomide unless the patient has histologically proven tumor recurrence.