IRB Study Number 23-786
Status Recruiting
Institute Taussig Cancer Institute
Description
Primary Objective
• To find optimal biological dose (OBD) based on efficacy and safety of each dosing group.
• To measure objective response rates (ORR) of = or >2nd line treatment of AL8326 for SCLC patients in all dosing groups and OBD group plus expansion cohort.
Secondary Objective
• To measure duration of response (DOR) for = or >2nd line treatment of AL8326 for SCLC patients in all dosing groups and OBD group plus expansion cohort. Progression Free Survival (PFS). To characterize PK profile of single dose and multiple doses, and PK/PD/Efficacy/Safety exposure relationship. Biomarker exploratory study.
Inclusion Criteria
Male or female, 18 years of age or older
ECOG performance status of 0 or 1
Histologically or cytologically confirmed SCLC[Patients who do not have histology samples (defined as core or excisional biopsy, or resections) will need to undergo a new biopsy to provide a tissue sample.]
Have limited-stage SCLC or extensive stage disease of SCLC by the American Joint Committee on Cancer, Seventh Edition
Patients of limited-stage SCLC or extensive-stage SCLC have received at least one line of prior SOC therapy which is atezolizumab or durvalumab in additional to platinum-based chemotherapy. Limited-stage patients who received first line platinum-based chemotherapy and subsequently had disease progression 6 months or more after their last first line therapy treatment must be required to have received platinum-based chemotherapy again prior to study enrollment.
Have at least 1 lesion that meets the criteria for being measurable, as defined by RECIST 1.1, and is appropriate for selection as a target lesion, as determined by local site investigator/radiology review. Lesions that appear measurable, but have undergone palliative irradiation, cannot be target lesions
Have a life expectancy of at least 3 months
Able to take orally administered study medication
Have adequate organ function as indicated by the following laboratory values
a. Bone marrow function: absolute neutrophil count (ANC) ≥1,500/mm3, platelets ≥100,000/mm3
b. b. Renal function: creatinine ≤1.5 x institutional upper limit normal (ULN) or if creatinine is >1.5 x ULN, creatinine clearance (per Cockcroft-Gault or other acceptable method) must be >60 mL/min.
c. c. Hepatic function: bilirubin ≤1.5 x ULN or ≤3.0 x ULN for patients with Gilbert Syndrome; AST and ALT ≤ 3.0 × ULN.
d. Coagulation profile: international normalized ratio (INR) is ≤1.5 and an aPTT or PTT <1.2 x ULN, unless on therapeutic anticoagulation
- If female subject of childbearing potential, have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication as needed. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required
Women of child-bearing potential must agree to use contraceptive measures starting from 1 week before the treatment until 4 weeks after the last dose of study treatment
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
- If male with female partner of childbearing potential, agree to use an adequate method of contraception, starting from 1 week before the treatment until 4 weeks after the last dose of study treatment
Note: Abstinence is acceptable if this is the usual lifestyle and preferred contraception for the subject
Have voluntarily agreed to participate by giving written informed consent/assent for the trial
amenable to undergoing strongly recommended biopsies if participating in the Phase 2 study (exception see Section 6.6)
Exclusion Criteria
Serious, non-healing wound, ulcer or bone fracture
Major surgical procedure within 28 days or minor surgical procedure performed within 7 days prior to treatment
Active bleeding or pathologic conditions that carry high risk of bleeding, such as known bleeding disorder, coagulopathy, or tumor involving major vessels
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.Patients with metastatic CNS tumors may participate in this study if the patient 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
Proteinuria on urinalysis within 28 days of enrollment. Patients 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 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
Women who are pregnant or nursing
Clinically significant, uncontrolled hypokalemia, hypomagnesaemia, and/or hypocalcemia
Hemoptysis within 3 months prior to enrollment
Acute or chronic liver disease, active hepatitis A or B with known cirrhosis or liver dysfunction
Cytotoxic chemotherapy, immunotherapy, or radiotherapy within 28 days (42 days in cases of mitomycin C, nitrosourea, lomustine) 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 history of human immunodeficiency virus infection (HIV)
Active bacterial infections requiring systemic antibiotics (excluding uncomplicated urinary tract infection)
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
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 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 of enrollment
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 mmHg pressure
QTc >470 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
Baseline echocardiogram (within 56 days of enrollment) 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 AL8326
Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
Pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study starting with the screening visit through 120 days after the last dose of pembrolizumab or saline placebo or up to 180 days after last dose of chemotherapeutic agents, whichever is later
History of pancreatitis; history of renal disease that includes histologically confirmed glomerulonephritis, biopsy proven tubulointerstitial nephritis, crystal nephropathy or other renal insufficiencies
Treatment with an investigational agent within 28 days of enrollment
Anticoagulation therapy with warfarin. Patients treated with heparin, low molecular weight heparin, or any other anticoagulant may be included provided the patient has been on a stable therapeutic dose of the anticoagulant for at least 14 days prior to enrollment
Known hypersensitivity to AL8326 or components of the formulation 31. Patients with well-controlled viral infections can be enrolled in this phase 2 expansion cohort after OBD determination. Refer to the FDA guidance “Cancer Clinical Trial Eligibility Criteria: Patients with HIV, Hepatitis B Virus, or Hepatitis C Virus Infections Guidance for Industry.” https://www.fda.gov/media/121319/download
