CD30biAb-AATC for CD30+ Malignancies

Study Overview
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Brief Summary
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This first-in-human trial will assess the safety, feasibility, and efficacy of an immunotherapy with a novel CD30 antibody conjugated to a CD3 antibody that is preloaded onto a patient's own T-cells, generating a CD30 bispecific antibody-armed, anti-CD3-activated, autologous T-cells (CD30 biAb-AATC).

Detailed Description
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Non-randomized, single arm, dose escalating, Phase I study evaluating the feasibility and safety of a novel anti-CD30 biAb-AATC product for children and young adult patients with relapsed/refractory CD30+ cancer. Following T-cell collection patients are recommended to receive a bridging chemotherapy for 21 days while product is being generated and quality control assessed. Patients will then undergo weekly administration of dose escalating CD30 biAb-AATC infusions with twice weekly subcutaneous GM-CSF in 4-week cycles for a maximum of two total cycles.

Official Title
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Phase I Dose-escalating Study to Investigate Safety, Tolerability, and Efficacy of Anti-CD30 Bispecific Antibody-armed Anti-CD3-Activated Autologous T-cells in Pediatric and Young Adult Patients With Relapsed/Refractory CD30+ Malignancies

Conditions
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Pediatric Cancer, Hodgkin Disease, CD30-Positive Diffuse Large B-Cell Lymphoma, CD30+ Anaplastic Large Cell Lymphoma, CD30+ Pleomorphic Large T-Cell Cutaneous Lymphoma, CD30+ Immunoblastic Large T-Cell Cutaneous Lymphoma, Neuroblastoma, Germ Cell Tumor, Extragonadal, Chondrosarcoma, Leukemia, Solid Tumor, Lymphoma

Intervention / Treatment
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* Drug: anti-CD30 Bispecific Antibody-armed anti-CD3-Activated Autologous T-cells (CD30 biAb-AATC)


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Diagnosis: Patients must have had histologic or cytologic verification of a qualified malignancy at original diagnosis. Patients must have histologic or cytologic verification of recurrence at relapse. No additional biopsy is required for patients with primary refractory diseases. The pathology report for the diagnosis under which the patient is being enrolled and associated molecular diagnostic reports must be submitted. CD30 Expression Status : Disease specific histologic, cytologic, or Fluorescence-Activated Cell Sorting (FACS)-confirmed CD30 cell surface expression on malignant cells is required. Disease Status: i. Solid Malignancies: Patients must have either measurable or evaluable disease based on the Response Evaluation Criteria in Solid Tumors (RECIST v1.1) criteria from the NCI for assessment of radiographic response. ii. Lymphomas: Patients must have measurable disease for assessment of radiographic response. iii. Leukemias: Patients must have ≥ 5% (M2 or M3) bone marrow blasts with or without extramedullary disease. In the case of an inadequate aspirate sample (dry tap), flow cytometry of peripheral blood specimen may be substituted if the patient has at least 1000/uL circulating blasts. Therapeutic Options: Patient's current disease state must be one for which there are no standard curative therapies or therapies proven to prolong survival with an acceptable quality of life. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all prior anticancer chemotherapy, defined as resolution of all such toxicities to ≤ Grade 2 or lower per the inclusion/exclusion criteria prior to entering this study Age: Patients must be >12 months and ≤39 years at time of study enrollment. Life Expectancy: Life expectance of >12 weeks. Performance Status: Karnofsky ≥50% for patients >16 years of age and Lansky ≥50 for patients ≤16 years of age. Note: Neurologic deficits in patients with CNS tumors must have been stable for at least 7 days prior to study enrollment. Patients who are unable to walk because of paralysis, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. Organ Function Requirements: Have acceptable organ function Pregnancy: It is not known what effects this treatment has on human pregnancy or development of the embryo or fetus. Therefore, female patients participating in this study should avoid becoming pregnant, and male patients should avoid impregnating a female partner. Non-sterilized female patients of reproductive age and male patients should use effective methods of contraception through defined periods during and after study treatment Consent: Ability to under understand a written informed consent document, and the willingness to sign it. Voluntary written consent will be documented before initiation of study-related procedures not part of normal medical care. Consent may be withdrawn by the subject/guardian without prejudice to future medical care. Exclusion Criteria: Prior Therapy: Any toxicities from prior treatment, >Grade 2 per CTCAE v5.0 Investigational Agent: Treatment with any investigational agent within 14 days of enrollment. Exclusion Requirements Due to Comorbid Disease or Concurrent Illness: Immune: Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. Steroid premedication for imaging scans is allowed. Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Infectious: Systemic fungal, bacterial, viral, or other infection not controlled (defined as exhibiting ongoing signs/symptoms related to the infection and without improvement, despite appropriate antibiotics or other treatment). Patients with possible fungal infections must have had at least 2 weeks of appropriate anti-fungal antibiotics and be asymptomatic. Pulmonary: No current or prior history of anti-CD30 therapy related pulmonary toxicity. Neurologic: No current or prior history of progressive multifocal leukoencephalopathy (PML). Cardiac: Patients cannot be diagnosed with NYHA Class III or IV (Appendix 7) congestive heart failure, ventricular arrhythmias, or uncontrolled hypertension. Allergies: Known hypersensitivity or allergic reaction attributed to any of the components of CD30 biAb-AATC or to compounds of similar composition to CD30 targeted agent, or a bispecific Antibody-armed activated autologous T cell product. Pregnant or Breastfeeding: Pregnant or breastfeeding females will not be allowed to enroll on this study. Female patients with infants must agree not to breastfeed their infants during the entire study treatment period and through three months after the last study drug dose. Agents used in this study are known to be teratogenic to a fetus. There is there is no information on the excretion of CD30 biAb-AATC agents into breast milk but potential risk for adverse events in nursing infants secondary to treatment of the mother with a CD30 biAb-AATC. Secondary Malignancy: Patients should not have a history of any second malignancy in the last 5 years with exception of the diagnosis for inclusion; subjects with prior history of in situ cancer or basal or squamous cell skin cancer are eligible. Subjects with other malignancies are eligible if they have been continuously disease free for at least 5 years.

Ages Eligible for Study
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Minimum Age: 1 Year
Maximum Age: 39 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: CD30biAb-AATC<br>Patients will undergo weekly administration of dose escalating CD30 biAb-AATC infusions with twice weekly subcutaneous GM-CSF in 4-week cycles for a maximum of two total cycles. | Drug: anti-CD30 Bispecific Antibody-armed anti-CD3-Activated Autologous T-cells (CD30 biAb-AATC)<br>* anti-CD30 Bispecific Antibody-armed anti-CD3-Activated Autologous T-cells (CD30 biAb-AATC)<br>* Other names: CD30 biAb-AATC;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose | To determine the MTD and recommended Phase II dose of CD30 biAb-AATC administered once weekly for a total of 4 doses per cycle | 3 years | 
| Define Toxicities - CTCAE v5.0 | To define the toxicities of CD30 biAb-AATC with twice weekly subcutaneous GM-CSF | 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics of CD30 biAb-AATC - Cmax | To define the circulating pharmacokinetics of CD30 biAb-AATC with twice weekly subcutaneous GM-CSF. Determination of peak plasma concentration | 3 years | 
| Pharmacokinetics of CD30 biAb-AATC - AUC(0-28day) | To define the circulating pharmacokinetics of CD30 biAb-AATC with twice weekly subcutaneous GM-CSF. Determination of persistence through AUC (0-28 day) | 3 years | 
| Define anti-tumor activity - Time-to-event efficacy | Within the confines of this Phase I study, to define the antitumor activity of anti-CD30 biAb-AATC in patients with CD30+ recurrent and/or refractory malignancies | 3 years | 
| Define anti-tumor activity - Objective Response Rate | Within the confines of this Phase I study, to define the antitumor activity of anti-CD30 biAb-AATC in patients with CD30+ recurrent and/or refractory malignancies | 3 years | 
| In vitro activity - quantitative cytotoxicity | To define the in vitro antitumor activity of a primary patient CD30 biAb-AATC product against standardized CD30+ cellular targets | 3 years | 
| Pediatric Patient Reported Outcomes - PROMIS Pediatric 25 Profile Version 2.0 | To define the pediatric patient reported outcomes for tolerability receiving a CD30 biAb-AATC product with twice weekly subcutaneous GM-CSF. Ages 5-7 will be PROMIS Pediatric 25 Profile version 2.0 caregiver proxy. Ages 8-17 will have PROMIS Pediatric 25 Profile version 2.0 and PROMIS Pediatric version 2.0 caregiver proxy. | 3 years | 
| Patient Reported Outcomes - PROMIS 29 Profile Version 2.1 | To define the patient reported outcomes for tolerability receiving a CD30 biAb-AATC product with twice weekly subcutaneous GM-CSF. Ages 18+ will receive PROMIS 29 Profile version 2.1 | 3 years | 
| Collection and Expansion Feasibility - Success Rate Whole blood | To determine the collection feasibility, T-cell yield, and manufacture/expansion time from venous catheter collections of whole blood without apheresis. Success rate for generation of adequate cell number for appropriate dose level product generation. | 3 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Pediatric, Young Adult, CD30, Cancer, Bispecific, Cellular Therapy, T Cell, autologous, relapse, refractory