A Study to Assess the Safety and Efficacy of ASP1650, a Monoclonal Antibody Targeting Claudin 6 (CLDN6), in Male Subjects With Incurable Platinum Refractory Germ Cell Tumors

Study Overview
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Brief Summary
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The purpose of this study was to establish the recommended phase 2 dose (RP2D) of ASP1650 (Safety Lead-in Phase), as well as, evaluate the efficacy of ASP1650 as measured by confirmed objective response rate (ORR) (phase 2) in participants with incurable platinum refractory germ cell tumors. This study also evaluated the following efficacy measures for confirmed objective response rate (ORR); clinical benefit rate (CBR); duration of response (DOR); and progression-free survival (PFS); as well as safety and tolerability; the effect of ASP1650 on changes in serum beta human chorionic gonadotropin (βhCG) and alpha-fetoprotein (AFP); and the pharmacokinetics of ASP1650.

Detailed Description
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The study consisted of 2 phases: Safety Lead-in phase and phase 2. 19 participants were enrolled in both phases. The Safety Lead-in phase of this study was to establish the tolerability of RP2D. The RP2D determination was based on at least 6 evaluable participants at the RP2D as determined by the Dose Evaluation Committee (DEC). Once RP2D had been established as tolerable, 13 additional participants were enrolled in phase 2 to receive ASP1650 for up to a maximum of 12 cycles or until a study discontinuation criteria had been met, whichever occurred earlier.

Official Title
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A Phase 2, Open-Label, Single-Arm, Multicenter Study to Assess the Safety and Efficacy of ASP1650, a Monoclonal Antibody Targeting Claudin 6 (CLDN6), in Male Subjects With Incurable Platinum Refractory Germ Cell Tumors

Conditions
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Incurable Platinum Refractory Germ Cell Tumors, Tumors

Intervention / Treatment
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* Drug: ASP1650


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: A male subject with female partner(s) of child-bearing potential must agree to use contraception during the treatment period and for at least 6 months after the final study drug administration. Subject must not donate sperm during the treatment period and for 6 months after the final study treatment administration. A male subject with a pregnant or breastfeeding partner(s) must agree to remain abstinent or use a condom for the duration of the pregnancy or time partner is breastfeeding throughout the study period and for 6 months after the final study treatment administration. Subject agrees not to participate in another interventional study while receiving study drug in present study. Disease Specific Criteria: Subject has histological evidence of germ cell tumor. Subject must have a germ cell tumor that is not amenable to cure with either surgery or chemotherapy. Subjects with seminoma and non-seminoma are eligible. Subject must have received initial cisplatin based combination chemotherapy AND demonstrated progression following at least 1 salvage regimen for advanced germ cell neoplasm (including relapsed primary mediastinal nonseminomatous germ cell tumor). Initial cisplatin based combination therapy includes bleomycin-etoposide-cisplatin, cisplatin-etoposide, etoposide-ifosfamide-cisplatin or similar regimens. Salvage regimens include high dose chemotherapy, paclitaxel-ifosfamide-cisplatin, vinblastine-ifosfamide cisplatin or similar regimens Failure of prior therapy is defined as: A > 25% increase in the products of perpendicular diameters of measurable tumor masses during prior therapy, which are not amenable to surgical resection; OR the presence of new tumor that are not amenable to surgical resection; OR an increase in alpha-fetoprotein (AFP) or beta human chorionic gonadotropin (βhCG) (≥ 50% increase in 2 separate samples collected at least 1 week apart are required if rising tumor markers are the only evidence of failure). NOTE: Subjects with clinically growing teratoma (enlarging mature teratoma arising during or after chemotherapy for a non seminomatous germ-cell tumor and with normal serum levels of AFP and βhCG) should undergo surgical resection if feasible. Subjects with late relapse (> 2 years) not amenable to resection are eligible. Subjects must have evidence of recurrent or metastatic carcinoma by 1 or more of the following: Subject has measurable disease according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 within 28 days prior to the first dose of study treatment. For subjects with only 1 measurable lesion and prior radiotherapy, the lesion must be outside the field of prior radiotherapy or must have documented progression following radiation therapy. Subject has a baseline rising tumor marker (AFP or βhCG). NOTE: If a rising tumor marker is the only evidence of progressive disease, at least 2 consecutive rising values at least 1 week apart are needed. Subjects with only evidence of disease as rising tumor marker AFP and βhCG will be assessed for alternate causes of increased serum levels of these markers, such as cross reaction with luteinizing hormone (LH) (can be tested if needed by testosterone suppression of LH), hepatitis, use of marijuana or second primary tumor. Physical or Laboratory Findings: Subject must have an available tumor specimen in a tissue block or unstained serial slides, or subject is an appropriate candidate for tumor biopsy and is amenable to undergoing a tumor biopsy during the screening period. Subject has Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2. Subject must meet all of the following criteria based on the centrally analyzed laboratory tests within 14 days prior to the first dose of study treatment. If repeat screening labs are required, local laboratory results can be used to confirm eligibility. In case of multiple central laboratory data within this period, the most recent data should be used to determine eligibility. Hemoglobin ≥ 8 g/dL Absolute neutrophil count (ANC) ≥ 1.0 x 109/L Platelets ≥ 75 x 109/L Albumin ≥ 2.5 g/dL Total bilirubin ≤ 2 x upper limit of normal (ULN) or direct bilirubin ≤ ULN for subjects with total bilirubin levels > 2 x ULN Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN without liver metastases (or ≤ 5 x ULN if liver metastases are present) Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2 Prothrombin time/international normalized ratio (PT/INR) and partial thromboplastin time (PTT) ≤ 2 x ULN (except for subjects receiving anticoagulation therapy) Exclusion Criteria: Prohibited Treatment or Therapies: Subject has received systemic immunosuppressive therapy, including systemic corticosteroids within 14 days prior to first dose of study treatment. Subject using a physiologic replacement dose of hydrocortisone or its equivalent (defined as up to 30 mg per day of hydrocortisone or up to 10 mg per day of prednisone) is eligible. Subject who received systemic steroids for asymptomatic central nervous system (CNS) metastases within 14 days prior to first dose of study treatment is eligible. Subject has received other investigational agents or devices within 28 days prior to first dose of study treatment. Subject has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 1 or at baseline) from adverse event (AE) due to monoclonal antibody (mAb) agents administered more than 4 weeks earlier. Subject has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study day 1 or who has not recovered (i.e., ≤ grade 2 or at baseline) from AEs due to a previously administered agent. Medical History or Concurrent Disease: Subject has prior severe allergic reaction or intolerance to a monoclonal antibody, including humanized or chimeric antibodies requiring permanent discontinuation. Subject has known immediate or delayed hypersensitivity, intolerance or contraindication to any component of study treatment. Subject has an active human immunodeficiency virus (HIV) infection or known active hepatitis B (HBsAg) or C infection. Subjects with well-controlled HIV infections (i.e., without detectable viral load) are eligible. For subjects who are negative for HBsAg, but hepatitis B core antibody (HBcAb) positive, an HBsAg deoxyribonucleic acid (DNA) test will be performed and if positive, the subject will be excluded. Subjects with positive serology but negative hepatitis C virus (HCV) ribonucleic acid (RNA) test results are eligible. Subject has active infection requiring systemic therapy that has not completely resolved within 14 days prior to first dose of study treatment. Subject has symptomatic central nervous system (CNS) metastases and/or carcinomatous meningitis. Subject with asymptomatic CNS metastases is eligible. Subject has had a major surgical procedure and has not completely recovered within 28 days prior to the first dose of study treatment. Subject has psychiatric illness or social situations that would preclude study compliance. Subject has another malignancy for which treatment is required. Subject with negligible risk of metastasis or death is eligible (e.g., basal or squamous cell skin cancer, localized prostate cancer treated with curative intent or incidental prostate cancer T1-T2a, Gleeson ≤ 3 + 4, PSA ≤ 0.5 and who are undergoing active surveillance). Subject has any concurrent disease, infection, or co-morbid condition that interferes with the ability of the subject to participate in the study, which places the subject at undue risk or complicates the interpretation of data.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Male

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: ASP1650, Dose Level 1<br>Participants received ASP1650 dose level 1 as intravenous infusion, every two weeks (Q2W) starting on Cycle 1 Day 1(C1D1) for up to a maximum of 12 cycles, or until disease progression, toxicity requiring study treatment cessation, start of another anticancer treatment, or until study discontinuation criteria was met, whichever occurred earlier. Duration of each treatment cycle was 14 days. | Drug: ASP1650<br>* Participants received ASP1650 dose level 1 or dose level 2 as intravenous infusion, Q2W starting on C1D1 for up to a maximum of 12 cycles or until study discontinuation criterion was met, whichever occurred earlier. Duration of each treatment cycle was 14 days.<br>|
| Experimental: ASP1650, Dose Level 2<br>Participants received ASP1650 dose level 2 as intravenous infusion, Q2W starting on C1D1 for up to a maximum of 12 cycles or until study discontinuation criteria as met, whichever occurred earlier. Duration of each treatment cycle was 14 days. | Drug: ASP1650<br>* Participants received ASP1650 dose level 1 or dose level 2 as intravenous infusion, Q2W starting on C1D1 for up to a maximum of 12 cycles or until study discontinuation criterion was met, whichever occurred earlier. Duration of each treatment cycle was 14 days.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose (RP2D) of ASP1650 | The RP2D was determined via dose limiting toxicity (DLT) assessment by dose evaluation committee (DEC). DLT was evaluated according to National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI-CTCAE) version 5.0. | Up to 28 days | 
| Percentage of Participants With Confirmed Objective Response by Modified RECIST v1.1 | Confirmed objective response was defined as the confirmed completed response (CR) or confirmed partial response (PR), as confirmed by investigator based on modified Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Per modified RECIST v1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Both Alpha-Fetoprotein (AFP) and Beta Human Chorionic Gonadotropin (beta-HCG) values were below the ULN. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. No increase ≥ 50% in 2 samples at least 1 week apart compared to nadir values for both AFP and beta-HCG. | From randomization until confirmed CR or confirmed PR, whichever occurred first (up to 26.57 weeks) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Percentage of Participants With Confirmed Objective Response by RECIST v1.1 | Confirmed objective response was defined as the confirmed CR or PR, as confirmed by investigator based on RECIST v1.1. Per RECIST v1.1, CR: disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. | From randomization until confirmed CR or confirmed PR, whichever occurred first (up to 26.57 weeks) | 
| Percentage of Participants With Clinical Benefit by Modified RECIST v1.1 and RECIST v1.1 | Clinical benefit: defined as best overall response of confirmed CR, confirmed PR, or durable stable disease (SD) as confirmed by investigator based on modified RECIST v1.1 and RECIST v1.1. Per RECIST v1.1 and modified RECIST V1.1, CR: disappearance of all target lesions. Any pathological lymph nodes(whether target or non-target) must have reduction in short axis to <10 mm. PR:at least a 30% decrease in sum of diameters of target lesions, taking as reference baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease, taking as reference smallest sum diameters while on study. Durable SD: SD maintained for at least 12 weeks. Additionally, per modified RECIST v1.1, CR also included AFP and beta-HCG values below ULN. PR also included no increase ≥ 50% in 2 samples at least 1 week apart compared to nadir values both for AFP and beta-HCG. | From randomization until confirmed CR, confirmed PR, or durable SD whichever occurred first (up to 26.57 weeks) | 
| Duration of Response (DOR) by Modified RECIST v1.1 and RECIST v1.1 for Dose Level 2 | DOR was defined as the time from the date of the first confirmed response CR or confirmed PR (whichever was first recorded) as confirmed by investigator based on modified RECIST 1.1 and RECIST v1.1 to the date of disease progression or date of censoring, whichever was earlier. If a participant had not progressed, participant was censored at the date of last disease assessment or at the date of first confirmed CR/PR if no post-baseline disease assessment was available. DOR (in days) was calculated as: (Date of documented progressive disease [PD], death, or censoring) minus (Date of the first CR/PR which was subsequently confirmed) +1. Duration of response was planned to summarized only for participants receiving dose level 2 in phase 2. | From randomization until confirmed CR or confirmed PR whichever occurred first (up to 26.57 weeks) | 
| Progression-Free Survival (PFS) by Modified RECIST v1.1 and RECIST v1.1 for Dose Level 2 | PFS was defined as the time from the date of first dose until the date of disease progression, or until death due to any cause. If a participant had neither progressed nor died, the participant was censored at the date of last disease as confirmed by investigator based on modified RECIST v1.1 and RECIST v1.1. The distribution of PFS was planned to be summarized only for participants receiving dose level 2 using Kaplan-Meier methodology. Per modified RECIST v1.1 and RECIST v1.1, Progressive disease (PD): appearance of one or more new lesions or at least a 20% increase in sum of diameters of target lesions, taking as reference smallest sum on study (this includes the baseline sum if that is the smallest on study). Also, the sum must be an absolute increase of at least 5 mm. Additionally per modified RECIST v1.1, PD was increase ≥ 50% in serum tumor markers AFP or beta-hCG in 2 samples at least 1 week apart compared to nadir values. | From the date of first dose until the date of disease progression, or until death due to any cause (up to 26.57 weeks) | 
| Number of Participants With Adverse Events (AEs) | An AE was defined as any untoward medical occurrence in a participant administered with an Investigational Product (IP) which does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign including abnormal laboratory finding/test result or other safety assessment, symptom, or disease temporally associated with use of IP whether or not considered related to IP. A treatment-emergent adverse event (TEAE) was defined as an AE with onset at any time from first dosing until last scheduled procedure. AEs were considered serious (SAEs) if AE resulted in death, was life-threatening, resulted in persistent or significant disability/incapacity or substantial disruption of the ability to conduct normal life functions, resulted in congenital anomaly, birth defect, or required inpatient hospitalization or led to prolongation of hospitalization. | From first dose of study drug up to 30 days after the last dose of study drug (up to 41.14 weeks) | 
| Number of Participants With Shifts From Baseline to Post Baseline in Eastern Cooperative Oncology Group Performance Status (ECOG PS) | Number of participants with shifts from baseline to post baseline in ECOG PS levels were reported. ECOG has 6 levels (0-5). Level 0 is fully active, able to carry on all pre-disease performance without restriction; Level 1 is restricted in physically strenuous activity but ambulatory ad able to carry out work of a light or sedentary nature, e.g. light house work, office work; Level 2 is ambulatory and capable of all self care but unable to carry out any work activities; up and about more than 50% of waking hours; Level 3 is capable of only limited self care; confined to bed or chair more than 50% of waking hours; Level 4 is completely disabled; cannot carry on any self care; totally confined to bed or chair); and Level 5 is dead. | Baseline, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1 (Duration of each treatment cycle was 14 days) | 
| Change From Baseline in Serum Beta Human Chorionic Gonadotropin (βhCG) | Blood was drawn for the measurement of serum βhCG at day 1 of every cycle (14 day cycle) to align with imaging assessment until the participant develops radiological disease progression per RECIST v1.1 evaluation or starts other systemic anticancer treatment. To evaluate the effect of ASP1650 on changes in serum βhCG, disease response was derived for participants with elevated serum tumor markers at baseline using CR, PR and SD. | Baseline, Cycle 2 Day 1 (C2D1), C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1 (duration of each cycle was 14 days) | 
| Change From Baseline in Serum Alpha-Fetoprotein (AFP) | Blood was drawn for the measurement of serum AFP at day 1 of every cycle (14 day cycle) to align with imaging assessment until the participant develops radiological disease progression per RECIST v1.1 evaluation or starts other systemic anticancer treatment. To evaluate the effect of ASP1650 on changes in serum AFP, disease response was derived for participants with elevated serum tumor markers at baseline using CR, PR and SD. | Baseline, C2D1, C3D1, C4D1, C5D1, C6D1, C7D1, C8D1, C9D1, C10D1, C11D1, C12D1 (duration of each cycle was 14 days) | 
| Pharmacokinetics (PK) of ASP1650 in Plasma: Area Under the Concentration-Time Curve Over 336 Hours (AUC336) | AUC336 was derived from the Pharmacokinetic (PK) plasma samples collected. Duration of each cycle was 14 days. | Dose Level 1 - CID1, C3D1: predose, 1.5 h after start of infusion, immediately after end of infusion, 0.5, 1.5, 3, 6, 24, 48, 72 h after end of infusion; Dose Level 2 - C1D1, C3D1: predose, immediately after end of infusion | 
| Pharmacokinetics (PK) of ASP1650 in Plasma: Maximum Concentration (Cmax) | Cmax was derived from the PK plasma samples collected. Duration of each cycle was 14 days. | Dose Level 1-CID1, C3D1: predose, 1.5 h after start of infusion, immediately after end of infusion, 0.5, 1.5, 3, 6, 24, 48, 72 h after end of infusion; Dose Level 2-C1D1, C3D1: predose, immediately after end of infusion | 
| Pharmacokinetics (PK) of ASP1650 in Plasma: Time to Maximum Concentration (Tmax) | Tmax was derived from the PK plasma samples collected. Duration of each cycle was 14 days. | Dose Level 1- CID1, C3D1: predose, 1.5 h after start of infusion, immediately after end of infusion, 0.5, 1.5, 3, 6, 24, 48, 72 h after end of infusion; Dose Level 2- C1D1, C3D1: predose, immediately after end of infusion | 
| Pharmacokinetics (PK) of ASP1650 in Plasma: Concentration Immediately Prior to Dosing at Multiple Dosing (Ctrough) | Ctrough was derived from the PK plasma samples collected. Duration of each cycle was 14 days. | C2D1,C3D1,C4D1,C5D1,C6D1,C7D1,C8D1,C9D1,C10D1,C11D1,C12D1:predose,1.5 h post start of infusion, immediately post end of infusion,0.5,1.5,3,6,24,48,72 h post end of infusion for Dose Level 1, and predose, immediately post end of infusion for Dose Level 2 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Incurable Platinum Refractory Germ Cell Tumors, ASP1650