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

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.

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.

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).

  1. Initial cisplatin based combination therapy includes bleomycin-etoposide-cisplatin, cisplatin-etoposide, etoposide-ifosfamide-cisplatin or similar regimens.
  2. "Salvage" regimens include high dose chemotherapy, paclitaxel-ifosfamide-cisplatin, vinblastine-ifosfamide cisplatin or similar regimens
  3. "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:

  1. 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.
  2. 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.

  1. Hemoglobin ≥ 8 g/dL
  2. Absolute neutrophil count (ANC) ≥ 1.0 x 109/L
  3. Platelets ≥ 75 x 109/L
  4. Albumin ≥ 2.5 g/dL
  5. Total bilirubin ≤ 2 x upper limit of normal (ULN) or direct bilirubin ≤ ULN for subjects with total bilirubin levels \> 2 x ULN
  6. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 x ULN without liver metastases (or ≤ 5 x ULN if liver metastases are present)
  7. Estimated glomerular filtration rate ≥ 30 mL/min/1.73 m2
  8. 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.