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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

NCT03760081

Description:

The purpose of this study is 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 will also evaluate 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.

Related Conditions:
  • Germ Cell Tumor
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: 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
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: 1650-CL-0201
  • NCT ID: NCT03760081

Conditions

  • Incurable Platinum Refractory Germ Cell Tumors
  • Tumors

Interventions

DrugSynonymsArms
ASP1650ASP1650 Escalation

Purpose

The purpose of this study is 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 will also evaluate 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

      The study consists of 2 phases: Safety Lead-in phase and phase 2. The Safety Lead-in phase of
      this study is to establish the tolerability of RP2D. Nine to 18 participants will be enrolled
      in the Safety Lead-in phase. The RP2D determination will be based on at least 6 evaluable
      participants at the RP2D as determined by the Dose Evaluation Committee (DEC).

      Once RP2D has been established as tolerable, up to 34 participants including participants
      from the RP2D cohort of the Safety Lead-in phase will be enrolled in phase 2 to receive
      ASP1650 for up to a maximum of 12 cycles or until a study discontinuation criteria has been
      met, whichever occurs earlier.
    

Trial Arms

NameTypeDescriptionInterventions
ASP1650 EscalationExperimentalAn initial dose level of ASP1650 (Safety Lead-in phase) will be evaluated in a 3-participant cohort and if well tolerated, a new 3- participant cohort will be opened at the next dose level according to the Bayesian Optimal Interval (BOIN) Design. The Dose Evaluation Committee will be responsible for the assessment of whether reduction or escalation should occur within the next cohort and/or to determine when maximum tolerated dose has been reached in a given dose level. Once the recommended phase 2 dose (RP2D) has been established as tolerable, up to 34 participants will be enrolled in phase 2 and will receive ASP1650 every 2 weeks starting on cycle 1/day 1 for up to a maximum of 12 cycles or until a study discontinuation criteria has been met, whichever occurs earlier.
  • ASP1650

Eligibility Criteria

        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-ifosfamidecisplatin, 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. 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) Either
                  serum creatinine ≤ 2.5 x ULN or 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Male
Healthy Volunteers:No

Primary Outcome Measures

Measure:Recommended phase 2 dose (RP2D) of ASP1650
Time Frame:Up to 28 Weeks
Safety Issue:
Description:The recommended phase 2 dose (RP2D) will be assessed through dose limiting toxicity (DLT) assessment by the Dose Evaluation Committee (DEC). A DLT is defined as adverse events or laboratory findings that cannot be clearly attributed to a cause other than study drug per the investigator.

Secondary Outcome Measures

Measure:Safety and tolerability assessed by nature, frequency, and severity of Adverse Events (AEs)
Time Frame:Up to 32 Weeks
Safety Issue:
Description:AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA). An AE is any untoward medical occurrence in a participant administered a study drug, and that does not necessarily have to have a causal relationship with this treatment. An AE can therefore be any unfavorable and unintended sign, symptom, or disease (new or exacerbated) temporally associated with the use of a medicinal product whether or not considered related to the medicinal product.
Measure:Number of participants with laboratory value abnormalities and/or adverse events (AEs)
Time Frame:Up to 28 Weeks
Safety Issue:
Description:Number of participants with potentially clinically significant laboratory values.
Measure:Number of participants with vital sign abnormalities and /or adverse events (AEs)
Time Frame:Up to 28 Weeks
Safety Issue:
Description:Number of participants with potentially clinically significant vital sign values.
Measure:Safety assessed by 12- lead electrocardiogram (ECG)
Time Frame:Up to 28 Weeks
Safety Issue:
Description:Prior to performing ECG, participants should rest in supine position for 10 minutes. ECG will be recorded as normal and abnormal and will be read locally.
Measure:Safety assessed by Eastern Cooperative Oncology Group (ECOG) performance status
Time Frame:Up to 28 Weeks
Safety Issue:
Description:The ECOG scale will be used to assess performance status. Scores range from 0 (Fully active, able to carry on all pre-disease performance without restriction) to 5 (Dead). Decrease in the score indicates an improvement. Increase in the score indicates a decline in performance.
Measure:Objective Response Rate (ORR) by RECIST v1.1
Time Frame:Up to 24 Weeks
Safety Issue:
Description:ORR is defined as the proportion of participants for each dose level whose best overall response is rated as confirmed complete response (CR) or partial response (PR) by modified RECIST v1.1.
Measure:Clinical Benefit Rate (CBR), as assessed by modified RECIST v1.1 and RECIST v1.1
Time Frame:Up to 24 Weeks
Safety Issue:
Description:CBR is defined as the proportion of participants for each dose level whose best overall response is rated as confirmed complete response (CR), partial response (PR) or durable stable disease (SD).
Measure:Duration of response, as assessed by modified RECIST v1.1 and RECIST v1.1
Time Frame:Up to 24 Weeks
Safety Issue:
Description:DOR is defined as the time from the date of the first response CR/PR (whichever is first recorded) to the date of progressive disease (PD) or date of censoring.
Measure:Progression-Free Survival (PFS), as assessed by modified RECIST v1.1 and RECIST v1.1
Time Frame:Up to 24 Weeks
Safety Issue:
Description:PFS is defined as the time from the date of first dose until the date of disease progression, or until death due to any cause.
Measure:Percent change in serum beta human chorionic gonadotropin (βhCG)
Time Frame:Up to 24 Weeks
Safety Issue:
Description:Blood will be drawn for the measurement of serum βhCG at day 1 of every cycle (14 day cycle). To evaluate the effect of ASP1650 on changes in serum βhCG, disease response will be derived for participants with elevated serum tumor markers at baseline using complete response (CR); partial response (PR) and stable disease (SD).
Measure:Percent change in serum alpha-fetoprotein (AFP)
Time Frame:Up to 24 Weeks
Safety Issue:
Description:Blood will be drawn for the measurement of serum AFP at day 1 of every cycle (14 day cycle). To evaluate the effect of ASP1650 on changes in serum AFP, disease response will be derived for participants with elevated serum tumor markers at baseline using complete response (CR); partial response (PR) and stable disease (SD).
Measure:Pharmacokinetics (PK) of ASP1650 in plasma: area under the concentration-time curve over 336 hours (AUC336)
Time Frame:Up to 42 days
Safety Issue:
Description:AUC336 will be derived from the PK plasma samples collected.
Measure:Pharmacokinetics (PK) of ASP1650 in plasma: maximum concentration (Cmax)
Time Frame:Up to 42 days
Safety Issue:
Description:Cmax will be derived from the PK plasma samples collected.
Measure:Pharmacokinetics (PK) of ASP1650 in plasma: time of maximum concentration (tmax)
Time Frame:Up to 42 days
Safety Issue:
Description:tmax will be derived from the PK plasma samples collected.
Measure:Pharmacokinetics (PK) of ASP1650 in plasma: the lowest concentration of drug achieved before the next dose is administered (Ctrough)
Time Frame:Up to 184 days
Safety Issue:
Description:Ctrough will be derived from the PK plasma samples collected.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Astellas Pharma Global Development, Inc.

Trial Keywords

  • Incurable Platinum Refractory Germ Cell Tumors
  • ASP1650

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