Pepinemab in Treating Younger Patients With Recurrent, Relapsed, or Refractory Solid Tumors

• ClinicalTrials.gov Identifier: NCT03320330
• Recruitment Status: Active, not recruiting
• First Posted: October 25, 2017
• Results First Posted: April 26, 2022
• Last Update Posted: October 5, 2023
• Sponsor: Children's Oncology Group
• Collaborator: National Cancer Institute (NCI)
• Information provided by (Responsible Party): Children's Oncology Group

Tracking Information

• First Submitted Date: October 13, 2017
• First Posted Date: October 25, 2017
• Results First Submitted Date: December 2, 2021
• Results First Posted Date: April 26, 2022
• Last Update Posted Date: October 5, 2023
• Actual Study Start Date: January 31, 2018
• Actual Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 22, 2022)

• Number of Participants With Dose Limiting Toxicities [ Time Frame: Up to 28 days ]
  Frequency (%) of patients with dose limiting toxicities by dose level and study part.
• Patients Who Had Grade 3 or Above Toxicities With the Three Attributions, 'DEFINITE', 'POSSIBLE','PROBABLE' [ Time Frame: Up to 28 days ]
  Frequency of patients experiencing at least grade 3 toxicity according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 by dose level and study part.
• Half-life [ Time Frame: Prior to, at the end of, and 2 hours after infusion on day 1 of cycles 1-2; days 4 & 8 of cycle 1; prior to and the end of infusion on day 15 of cycle 1; prior to start of infusion on day 15 of cycle 2; prior to start of infusion on day 1 of cycles 3+ ]
  Mean and standard deviation for the time required for the serum concentration to fall to 50% of its starting dose by dose level and study part.
• Time to Maximum Concentration (T Max) [ Time Frame: Prior to, at the end of, and 2 hours after infusion on day 1 of cycles 1-2; days 4 & 8 of cycle 1; prior to and the end of infusion on day 15 of cycle 1; prior to start of infusion on day 15 of cycle 2; prior to start of infusion on day 1 of cycles 3+ ]
  Mean and standard deviation for the time at which the maximum (peak) serum concentration occurs by dose level and study part.
• Maximum Concentration (C Max) [ Time Frame: Prior to, at the end of, and 2 hours after infusion on day 1 of cycles 1-2; days 4 & 8 of cycle 1; prior to and the end of infusion on day 15 of cycle 1; prior to start of infusion on day 15 of cycle 2; prior to start of infusion on day 1 of cycles 3+ ]
  Mean and standard deviation for the maximum (peak) serum concentration by dose level and study part.
• Area Under Curve (AUC) [ Time Frame: Prior to, at the end of, and 2 hours after infusion on day 1 of cycles 1-2; days 4 & 8 of cycle 1; prior to and the end of infusion on day 15 of cycle 1; prior to start of infusion on day 15 of cycle 2; prior to start of infusion on day 1 of cycles 3+ ]
  Mean and standard deviation for the area under the drug concentration over time curve by dose level and study part.
• Clearance [ Time Frame: Prior to, at the end of, and 2 hours after infusion on day 1 of cycles 1-2; days 4 & 8 of cycle 1; prior to and the end of infusion on day 15 of cycle 1; prior to start of infusion on day 15 of cycle 2; prior to start of infusion on day 1 of cycles 3+ ]
  Mean and standard deviation for the rate of elimination of the drug by dose level and study part.
• Disease Control Rate (Part A) [ Time Frame: Up to 4 months ]
  Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no new lesions detected and <20% increase in sum of smallest diameters of lesions; Disease Control Rate = CR + PR + SD
• Response (Complete Response or Partial Response) (Part B) [ Time Frame: Up to 168 days ]
  Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Stable Disease (SD), no new lesions detected and <20% increase in sum of smallest diameters of lesions; Disease Control Rate = CR + PR + SD

Original Primary Outcome Measures (submitted: October 20, 2017)

• Disease control rate (Part B) [ Time Frame: At 4 months ]
  Disease control success will be defined as complete response, partial response or stable disease.
• Incidence of toxicities of VX15/2503 (Parts A-B) [ Time Frame: Up to 3 years ]
  Will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
• Maximum tolerated dose (MTD) and/or recommended phase 2 dose of VX15/2503 (Part A) [ Time Frame: Up to 28 days ]
  Will be defined as the maximum dose at which fewer than one-third of patients experience dose limiting toxicities (DLT) and graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.
• Response (complete response [CR] or partial response [PR]) (Part B) [ Time Frame: Up to 3 years ]
  Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1.

Current Secondary Outcome Measures (submitted: February 13, 2023)

• T-lymphocyte Saturation [ Time Frame: Up to 28 days ]
  Mean and standard deviation for blood samples that will be evaluated for T-lymphocyte saturation by VX15/2503 utilizing a validated flow-cytometry based assay on cycle 1 day 28 (prior to cycle 2 day 1).
• Total Soluble SEMA4D [ Time Frame: Up to 28 days ]
  Mean and standard deviation of blood and serum samples evaluated for total soluble SEMA4D through a qualified enzyme-linked immunosorbent assay (ELISA) assay.
• Immunogenicity of Pepinemab [ Time Frame: Up to 3 years ]
  Mean and standard deviation of immunogenicity assessed in serum through a qualified ELISA.

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided

Original Other Pre-specified Outcome Measures (submitted: October 20, 2017)

• Pharmacokinetics to define systemic exposure of VX15/2503 in serum (Parts A-B) [ Time Frame: Prior to the start of infusion of each cycle of treatment (Cycle 1 and 2 will have two timepoints, Day 1 and 15). Each cycle will last 28 days. ]
  Will be assessed by a qualified enzyme-linked immunosorbent assay (ELISA). Will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
• Pharmacokinetics to define drug clearance of VX15/2503 in serum (Parts A-B) [ Time Frame: Prior to the start of infusion of each cycle of treatment (Cycle 1 and 2 will have two timepoints, Day 1 and 15). Each cycle will last 28 days. ]
  Will be assessed by a qualified enzyme-linked immunosorbent assay (ELISA). Will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit).
• Pharmacodynamics of VX15/2503 defined as VX15/2503 saturation of T-lymphocytes [ Time Frame: Up to 3 years ]
  Will be assessed in blood and will utilize a validated flow-cytometry based assay. Analyses will be descriptive and exploratory and hypotheses generating in nature.
• Immunogenicity of VX15/2503 [ Time Frame: Up to 3 years ]
  Will be assessed in serum through a qualified enzyme-linked immunosorbent assay (ELISA). Analyses will be descriptive and exploratory and hypotheses generating in nature.

Descriptive Information

• Brief Title: Pepinemab in Treating Younger Patients With Recurrent, Relapsed, or Refractory Solid Tumors
• Official Title: A Phase 1/2 Study of VX15/2503 in Children, Adolescents, or Young Adults With Recurrent or Relapsed Solid Tumors
• Brief Summary: This phase I/II trial studies the side effects and best dose of pepinemab and to see how well it works in treating younger patients with solid tumors that have come back after treatment, or do not respond to treatment. Immunotherapy with monoclonal antibodies, such as pepinemab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended phase 2 dose of pepinemab (VX15/2503) administered as an intravenous infusion every 14 days to children with recurrent or refractory solid tumors. (Part A) II. To define and describe the toxicities of VX15/2503 administered on this schedule. (Parts A-B) III. To characterize the pharmacokinetics of VX15/2503 in children with recurrent or refractory cancer. (Parts A-B) IV. To preliminarily define the antitumor activity of VX15/2503 for the treatment of relapsed or refractory osteosarcoma. (Part B) V. To determine if VX15/2503 either improves the disease control rate at 4 months in patients with recurrent measurable osteosarcoma or produces an objective response rate in patients with relapsed or refractory osteosarcoma. (Part B)

SECONDARY OBJECTIVES:

I. To assess the pharmacodynamics of VX15/2503 through VX15/2503 saturation of T-lymphocytes.

II. To assess the immunogenicity of VX15/2503 in pediatric patients with recurrent or refractory cancer.

EXPLORATORY OBJECTIVES:

I. To evaluate potential biomarkers of VX15/2503 sensitivity including SEMA4D, PlexinB1, and other markers of immune cell infiltration in archival tumor tissues.

OUTLINE: This is a phase I, dose-escalation study followed by a phase II study.

Patients receive pepinemab intravenously (IV) over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 13 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up periodically.

• Study Type: Interventional
• Study Phase: Phase 1; Phase 2
• Study Design: Allocation: N/A; Intervention Model: Single Group Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Recurrent Malignant Solid Neoplasm
• Recurrent Osteosarcoma
• Refractory Malignant Solid Neoplasm
• Refractory Osteosarcoma

Intervention

• Other: Laboratory Biomarker Analysis
  Correlative studies
• Biological: Pepinemab
  Given IV
  Other Names:

  • moAb VX15/2503
  • VX15/2503
• Other: Pharmacological Study
  Correlative studies

Study Arms

Experimental: Treatment (pepinemab)

Patients receive pepinemab IV over 60 minutes on days 1 and 15. Treatment repeats every 28 days for 13 cycles in the absence of disease progression or unacceptable toxicity.

Interventions:

• Other: Laboratory Biomarker Analysis
• Biological: Pepinemab
• Other: Pharmacological Study

• Publications *: Hattinger CM, Patrizio MP, Magagnoli F, Luppi S, Serra M. An update on emerging drugs in osteosarcoma: towards tailored therapies? Expert Opin Emerg Drugs. 2019 Sep;24(3):153-171. doi: 10.1080/14728214.2019.1654455. Epub 2019 Aug 14.

Recruitment Information

• Recruitment Status: Active, not recruiting
• Actual Enrollment (submitted: March 22, 2022): 26
• Original Estimated Enrollment (submitted: October 20, 2017): 75
• Estimated Study Completion Date: September 22, 2024
• Actual Primary Completion Date: December 31, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Part A: Patients with recurrent or refractory solid tumors are eligible, excluding central nervous system (CNS) tumors; patients must have had histologic verification of malignancy at original diagnosis or relapse
• Part B: Patients with recurrent or refractory osteosarcoma are eligible; patients must have had histologic verification of malignancy at original diagnosis or relapse
• Part A: Patients must have either measurable or evaluable disease
• Part B: Patients must have measurable disease
• Patient's current disease state must be one for which there is no known curative therapy or therapy proven to prolong survival with an acceptable quality of life
• Karnofsky >= 50% for patients > 16 years of age and Lansky >= 50 for patients =< 16 years of age; 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

• Patients must have fully recovered from the acute toxic effects of all prior anti-cancer therapy and must meet the following minimum duration from prior anti-cancer directed therapy prior to enrollment; if after the required timeframe, the numerical eligibility criteria are met, e.g. blood count criteria, the patient is considered to have recovered adequately

  • Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive

    • >= 21 days after the last dose of cytotoxic or myelosuppressive chemotherapy (42 days if prior nitrosourea)
  • Anti-cancer agents not known to be myelosuppressive (e.g. not associated with reduced platelet or absolute neutrophil count [ANC] counts): >= 7 days after the last dose of agent
  • Antibodies: >= 21 days must have elapsed from infusion of last dose of antibody, and toxicity related to prior antibody therapy must be recovered to grade =< 1
  • Corticosteroids: If used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of corticosteroid
  • Hematopoietic growth factors: >= 14 days after the last dose of a long-acting growth factor (e.g. pegfilgrastim) or 7 days for short-acting growth factor; for agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur; the duration of this interval must be discussed with the study chair and the study-assigned research coordinator
  • Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines (other than hematopoietic growth factors)

  • Stem cell Infusions (with or without total body irradiation [TBI]):

    • Allogeneic (non-autologous) bone marrow or stem cell transplant, or any stem cell infusion including donor lymphocyte infusion (DLI) or boost infusion: >= 84 days after infusion and no evidence of graft versus host disease (GVHD)
    • Autologous stem cell infusion including boost infusion: >= 42 days
  • Cellular Therapy: >= 42 days after the completion of any type of cellular therapy (e.g. modified T cells, natural killer [NK] cells, dendritic cells, etc.)
  • Radiation Therapy (XRT)/External Beam Irradiation including Protons: >= 14 days after local XRT; >= 150 days after TBI, craniospinal XRT or if radiation to >= 50% of the pelvis; >= 42 days if other substantial bone marrow (BM) radiation
  • Radiopharmaceutical therapy (e.g., radiolabeled antibody, 131I-MIBG): >= 42 days after systemically administered radiopharmaceutical therapy
• Patients must not have received prior exposure to VX15/2503
• Peripheral absolute neutrophil count (ANC) >= 1000/mm^3
• Platelet count >= 100,000/mm^3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
• Hemoglobin >= 8.0 g/dL at baseline (may receive red blood cell [RBC] transfusions)
• Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts above (may receive transfusions provided they are not known to be refractory to red cell or platelet transfusions); these patients will not be evaluable for hematologic toxicity; at least 5 of every cohort of 6 patients must be evaluable for hematologic toxicity for the dose-escalation part of the study; if dose-limiting hematologic toxicity is observed, all subsequent patients enrolled must be evaluable for hematologic toxicity
• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 ml/min/1.73 m^2 or

• A serum creatinine based on age/gender as follows:

  • Age: 1 to < 2 years; Male: 0.6 mg/dL; Female: 0.6 mg/dL
  • Age: 2 to < 6 years; Male: 0.8 mg/dL; Female: 0.8 mg/dL
  • Age: 6 to < 10 years; Male: 1 mg/dL; Female: 1 mg/dL
  • Age: 10 to < 13 years; Male: 1.2 mg/dL; Female: 1.2 mg/dL
  • Age: 13 to < 16 years; Male: 1.5 mg/dL; Female: 1.4 mg/dL
  • Age: >= 16 years; Male: 1.7 mg/dL; Female: 1.4 mg/dL
• Bilirubin (sum of conjugated + unconjugated) =< 1.5 x upper limit of normal (ULN) for age
• Alanine aminotransferase (ALT) serum glutamic pyruvic transaminase (SGPT) =< 135 U/L; for the purpose of this study, the ULN for ALT is 45 U/L
• Serum albumin >= 2 g/dL
• No clinical indications such as evidence of dyspnea at rest, or exercise intolerance due to pulmonary insufficiency
• If clinical indications, pulse oximetry > 94% on room air
• All patients and/or their parents or legally authorized representatives must sign a written informed consent; assent, when appropriate, will be obtained according to institutional guidelines
• Tissue blocks or slides must be sent; if tissue blocks or slides are unavailable, the study chair must be notified prior to enrollment

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study; pregnancy tests must be obtained in girls who are post-menarchal; males or females of reproductive potential may not participate unless they have agreed to use two effective methods of birth control, including a medically accepted barrier or contraceptive method (e.g., male or female condom) for the duration of the study; abstinence is an acceptable method of birth control
• Patients receiving systemic corticosteroids who have not been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment are not eligible; if used to modify immune adverse events related to prior therapy, >= 14 days must have elapsed since last dose of systemic corticosteroid; Note: patients who are using topical or inhaled corticosteroids are eligible
• Patients who are currently receiving another investigational drug are not eligible
• Patients who are currently receiving other anti-cancer agents are not eligible (except leukemia patients receiving hydroxyurea, which may be continued until 24 hours prior to start of protocol therapy)
• Patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post bone marrow transplant are not eligible for this trial
• Patients who have an uncontrolled infection are not eligible
• Patients who have received a prior solid organ transplantation are not eligible
• Patients who in the opinion of the investigator may not be able to comply with the safety monitoring requirements of the study are not eligible

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 12 Months to 30 Years (Child, Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States

Administrative Information

• NCT Number: NCT03320330
• Other Study ID Numbers: ADVL1614; NCI-2017-01103 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); ADVL1614 ( Other Identifier: Pediatric Early Phase Clinical Trial Network ); ADVL1614 ( Other Identifier: CTEP ); UM1CA097452 ( U.S. NIH Grant/Contract )
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Children's Oncology Group
• Original Responsible Party: Same as current
• Current Study Sponsor: Children's Oncology Group
• Original Study Sponsor: Same as current
• Collaborators: National Cancer Institute (NCI)

Investigators

• Principal Investigator: Emily G Greengard; COG Phase I Consortium

• PRS Account: Children's Oncology Group
• Verification Date: September 2023