A Phase I/II, Multi-center, Single-Arm, Open-Label Study to Evaluate the Safety and Efficacy of ALMB-0168 in Patients With Osteosarcoma
Overview
- Phase
- Phase 1
- Intervention
- ALMB-0168
- Conditions
- Osteosarcoma
- Sponsor
- AlaMab Therapeutics (Shanghai) Inc.
- Enrollment
- 238
- Primary Endpoint
- Incidence of adverse events
- Last Updated
- 4 years ago
Overview
Brief Summary
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
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.
Investigators
Eligibility Criteria
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.
- •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);
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;
Arms & Interventions
ALMB-0168
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.
Intervention: ALMB-0168
Outcomes
Primary Outcomes
Incidence of adverse events
Time Frame: From enrollment to 28 days after the last dose in each part study.
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.
Dose-Limited Toxicities (DLT)
Time Frame: Up to 21 days in Cycle 1
DLTs were assessed according to NCI-CTCAE v.5.0 during the first cycle
6-Month Progression-free Survival Rate (6m-PFSR)
Time Frame: From enrollment to 6 month after the first dose of the last patient in PART II
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.
Secondary Outcomes
- Change from baseline in Bone Mineral Density (BMD)(through study completion, an average of 3 year)
- Maximum concentration (Cmax) of ALMB-0168(From enrollment to 4 weeks after the last dose of the last patient)
- Time to maximum concentration (Tmax) of ALMB-0168(From enrollment to 4 weeks after the last dose of the last patient)
- Minimum concentration(Cmin) of ALMB-0168(From enrollment to 4 weeks after the last dose of the last patient)
- The area under the curve (AUC) of ALMB-0168(From enrollment to 4 weeks after the last dose of the last patient)
- Half-life (t1/2) of ALMB-0168(From enrollment to 4 weeks after the last dose of the last patient)
- Clearance (CL) of ALMB-0168(From enrollment to 4 weeks after the last dose of the last patient)
- Objective Response Rate (ORR)(2 year)
- Disease control rate (DCR)(2 year)
- Duration of response (DOR)(2 year)
- Progression-free survival (PFS)(up to 3 years)
- Time to Response (TTR)(2 year)
- Overall survival (OS)(up to 3 years)
- Rate of Skeletal Related Events (SRE)(through study completion, an average of 3 year)
- Change from baseline in alkaline phosphatase (ALP) and lactate dehydrogenase (LDH)(through study completion, an average of 3 year)
- Dose of morphine compared with baseline(through study completion, an average of 3 year)
- Frequency of morphine compared with baseline(through study completion, an average of 3 year)
- Change from baseline of numeric pain scale (NRS) scores(through study completion, an average of 3 year)
- Change from baseline of quality of life scale (EQ-5D) scores(through study completion, an average of 3 year)
- The incidence of anti-drug antibody (ADA)(From enrollment to 4 weeks after the last dose of the last patient)