A Study to Evaluate the Safety and Efficacy of ALMB-0168 in Patients With Osteosarcoma

Study Overview
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Brief Summary
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This is a phase I / II, multi-center, single-arm, open-label study to evaluate the safety and efficacy of ALMB-0168 in patients with osteosarcoma whose prior standard treatment have failed.

Detailed Description
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This is a phase I / II, multi-centre, single-arm, open-label study with two parts, a dose-escalation phase (Part I) and a dose-expansion phase (part II). In part I, patients with osteosarcoma whose prior standard treatment have failed will be assigned to receive sequentially higher doses of ALMB-0168 intravenously. The dose-escalation initially will follow an accelerated titration design for the first two dosing groups, then follow a classic 3+3 design. The maximum tolerated dose (MTD) and the recommended Phase 2 dose (RP2D) of ALMB-0168 will be determined in part I. In Part II, 1-3 expansion cohorts will begin to further assess the safety profile and explore efficacy, and each cohort will enroll up to 60 patients with high-grade osteosarcoma in each cohort. All patients will receive multiple administration of ALMB-0168 until either the disease progresses or intolerable toxicity occurs.

Official Title
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A Phase I/II, Multi-center, Single-Arm, Open-Label Study to Evaluate the Safety and Efficacy of ALMB-0168 in Patients With Osteosarcoma

Conditions
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Osteosarcoma

Intervention / Treatment
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* Drug: ALMB-0168


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histopathologically confirmed osteosarcoma; Patients will be enrolled according to different stages: Part I: Patients with osteosarcoma whose prior standard treatment have failed.; Part II: Patients with high-grade osteosarcoma whose prior standard treatment have failed.; Standard treatment failure is defined as the progression on or within 6 months after the first-line chemotherapy (including high-dose methotrexate, doxorubicin, cisplatin, ifosfamide, etc.); For patients with disease progression more than 6 months after the chemotherapy, the risk-benefit assessment should be conducted by the investigators; 16 years of age or older, male or female; Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1 or 2; Either measurable or non-measurable disease per RECIST v1.1. Non-measurable disease should be assessable by conventional imaging techniques including isotope bone scans, CT or MRI scans. Patients in part II stage must have at least one measurable lesion confirmed by CT or MRI at baseline. Adequate major system function defined as: Bone marrow reserve: Absolute neutrophil count (ANC) ≥1.5 x109/L; Platelet count ≥ 75 x 109/L; Hemoglobin ≥ 90 g/L (not receiving blood transfusion within 14 days before the first administration); Hepatic function: Total bilirubin ≤1.5 x upper limit of normal (ULN), Transaminases (aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT) and/or alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT)) ≤ 3 x ULN (<5 x ULN for liver metastases); Renal function: Normal serum creatinine ≤1.5 mg/dL (133 μmol/L) OR calculated creatinine clearance ≥50 mL/min. (Cockcroft - Gault formula); Coagulation: Adequate coagulation parameters defined as International Normalization Ratio (INR) ≤2. Female patients of childbearing potential must have negative results of serum pregnancy test within 7 days before the first dose. Male patients with female partners of childbearing potential and female patients of childbearing potential are required to use two forms of acceptable contraception, including 1 barrier method, during their participation in the study and for 3 months following the last dose. Male patients must also refrain from donating sperm during their participation in the study; Life expectancy ≥3 months; Ability to understand the entire process of this study, voluntarily participate and sign a written informed consent form. Exclusion Criteria: Any recent anti-tumour therapy ≤ 28 days before the first dose or residual more than Grade 1 chemotherapy-related side effects per NCI CTCAE v5.0, with the exception of alopecia. Have participated in the other clinical trial and received the investigational drug treatment within 4 weeks before the first dose of study drug; Wide-field radiotherapy (including therapeutic radioisotopes such as strontium 89) administered ≤28 days or limited field radiation for palliation ≤7 days prior to starting study drug or has not recovered from side effects of such therapy; Major surgical procedures ≤28 days of beginning study drug, or minor surgical procedures ≤7 days. No waiting required following port-a-cath placement; Brain metastases, leptomeningeal metastases or, spinal cord compression or central nervous system (CNS) injuries/abnormalities; Pregnant women. Breastfeeding women should stop breastfeeding before signing the informed consent; Any of the following cardiac diseases currently or within the last 6 months: Left ventricular ejection fraction (LVEF) <45% as determined by echocardiogram (ECHO); The corrected QT interval (Fridericia formula) interval (QTcF) > 470 msec for females and > 450 msec for men in electrocardiogram (ECG) at screening; Unstable angina pectoris; Heart failure (New York Heart Association (NYHA) >2 grade); Acute myocardial infarction; Uncontrolled arrhythmia; Acute coronary syndromes; Stent placement; Uncontrolled hypertension (systolic blood pressure (SBP) > 160 mmHg or diastolic blood pressure (DBP) > 100 mmHg (Patients with blood pressure values higher than these levels must use drugs to control blood pressure below this level before the first dose of study drug)); Have a serious active infection (systemic intravenous antibiotics within 14 days but oral antibiotics allowed) that is not well controlled, or have another serious underlying medical condition that would prevent the patients from receiving the protocol treatment; Known diagnosis of human immunodeficiency virus, active hepatitis B or C; Have received Chinese herbal medicine or Chinese patent drug with anti-tumor activity within 14 days before the first administration; Has other active tumors or a history of infiltrative tumor treatment within 3 years. Patients with a history of definitively locally treated stage I tumors who are considered unlikely to recur can be accepted. Patients with a history of prior treatment for carcinoma in situ (e.g., non-invasive) and history of non-melanoma skin cancer are acceptable. According to the researchers' judgment, patients with other factors that may lead to the termination of the study, such as other serious diseases (including severe mental disorders) requiring combined treatment, serious laboratory abnormalities, family or social factors, which may affect the safety or the collection of data and samples. Psychological, family, social or geographical conditions and other factors are not consistent with the experimental scheme.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ALMB-0168<br>Dose Escalation Cohort ：The accelerated titration and traditional 3+3 design will be used in the dose-escalation phase. Seven dose cohorts will be evaluated. ALMB-0168 will be administered intravenously once every 3 weeks until either the disease progresses or intolerable toxicity occurs. Dose Expansion Cohort: Based on the results of Part I, 1-3 dose expansion cohorts will be started to further evaluate the safety and efficacy of ALMB-0168. | Drug: ALMB-0168<br>* ALMB-0168 will be administered intravenously until either the disease progresses or intolerable toxicity occurs.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of adverse events | Defined by the Common Terminology Criteria for Adverse Events version 5.0 (CTCAE V5.0). Incidence of adverse events will be assessed in both PART I and PART II. | From enrollment to 28 days after the last dose in each part study. | 
| Dose-Limited Toxicities (DLT) | DLTs were assessed according to NCI-CTCAE v.5.0 during the first cycle | Up to 21 days in Cycle 1 | 
| 6-Month Progression-free Survival Rate (6m-PFSR) | 6m-PFSR is defined as the percentage of patients who will be alive and without PD at 6 months from the randomization date. 6m-PFSR will be assessed only in PART II. | From enrollment to 6 month after the first dose of the last patient in PART II | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum concentration (Cmax) of ALMB-0168 | Measure the maximum (peak) plasma concentration | From enrollment to 4 weeks after the last dose of the last patient | 
| Time to maximum concentration (Tmax) of ALMB-0168 | Measure the time to reach maximum (peak) plasma concentration | From enrollment to 4 weeks after the last dose of the last patient | 
| Minimum concentration(Cmin) of ALMB-0168 | Measure the minimum (trough) plasma concentration | From enrollment to 4 weeks after the last dose of the last patient | 
| The area under the curve (AUC) of ALMB-0168 | Measure the area under the curve | From enrollment to 4 weeks after the last dose of the last patient | 
| Half-life (t1/2) of ALMB-0168 | calculate the half-life of ALMB-0168 | From enrollment to 4 weeks after the last dose of the last patient | 
| Clearance (CL) of ALMB-0168 | Measure apparent total clearance(s) from plasma after administration | From enrollment to 4 weeks after the last dose of the last patient | 
| Objective Response Rate (ORR) | ORR will be assessed by Blinded Independent Review Committee (IRC) per RECIST Version 1.1. | 2 year | 
| Disease control rate (DCR) | DCR will be determined by Response evaluation criteria in solid tumours v1.1 | 2 year | 
| Duration of response (DOR) | DOR was defined as the time from first documented evidence of complete response (CR) or partial response (PR) until progressive disease (PD) or death. | 2 year | 
| Progression-free survival (PFS) | PFS was defined as the time from randomization to the first documented PD or death due to any cause, whichever occurred first. | up to 3 years | 
| Time to Response (TTR) | TTR was defined as the time to a confirmed CR (disappearance of all target lesions) or PR (At least a 30 percent decrease in the sum of diameters of target lesions) per RECIST 1.1. | 2 year | 
| Overall survival (OS) | OS was defined as the time from randomization to death due to any cause. | up to 3 years | 
| Rate of Skeletal Related Events (SRE) | Including pathological fractures, spinal cord compression, hypercalcemia caused by malignant tumors, radiotherapy or surgery for bone lesions for symptom relief | through study completion, an average of 3 year | 
| Change from baseline in alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) | pre- and post-treatment ALP and LDH changes in blood samples | through study completion, an average of 3 year | 
| Change from baseline in Bone Mineral Density (BMD) | Dual-energy X-ray absorptiometry (DXA) to determine the bone mineral density of the subjects' lumbar spine, hip bone and femoral neck. | through study completion, an average of 3 year | 
| Dose of morphine compared with baseline | pre- and post-treatment dose changes of morphine | through study completion, an average of 3 year | 
| Frequency of morphine compared with baseline | pre- and post-treatment frequency changes of morphine | through study completion, an average of 3 year | 
| Change from baseline of numeric pain scale (NRS) scores | pre- and post-treatment changes of NRS scores (min max: 0 10; higher scores means a worse outcome) | through study completion, an average of 3 year | 
| Change from baseline of quality of life scale (EQ-5D) scores | pre- and post-treatment changes of EQ-5D scores (min max: 0 100; higher scores means a better outcome) | through study completion, an average of 3 year | 
| The incidence of anti-drug antibody (ADA) | The percentage of patients with ADA | From enrollment to 4 weeks after the last dose of the last patient |