Clinical trial NCT03320330: 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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Recurrent Malignant Solid Neoplasm
Recurrent Osteosarcoma
Refractory Malignant Solid Neoplasm
Refractory Osteosarcoma
Lead sponsor: Children's Oncology Group
Sponsor class: NETWORK
Collaborators: name: National Cancer Institute (NCI)
First posted: 2017-10-25
Enrollment: 26
Sex: ALL
Minimum age (years): 12
Maximum age (years): 30
Standard ages: CHILD
ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Number of Participants With Dose Limiting Toxicities
timeFrame: Up to 28 days
measure: Patients Who Had Grade 3 or Above Toxicities With the Three Attributions, 'DEFINITE', 'POSSIBLE','PROBABLE'
timeFrame: Up to 28 days
measure: Half-life
timeFrame: 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+
measure: Time to Maximum Concentration (T Max)
timeFrame: 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+
measure: Maximum Concentration (C Max)
timeFrame: 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+
measure: Area Under Curve (AUC)
timeFrame: 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+
measure: Clearance
timeFrame: 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+
measure: Disease Control Rate (Part A)
timeFrame: Up to 4 months
measure: Response (Complete Response or Partial Response) (Part B)
timeFrame: Up to 168 days
Secondary outcomes:
measure: T-lymphocyte Saturation
timeFrame: Up to 28 days
measure: Total Soluble SEMA4D
timeFrame: Up to 28 days
measure: Immunogenicity of Pepinemab
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Children's Hospital of Alabama
state: Alabama
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: Orange
country: United States
facility: Children's Hospital of Orange County
state: California
city: San Francisco
country: United States
facility: UCSF Medical Center-Mission Bay
state: California
city: Aurora
country: United States
facility: Children's Hospital Colorado
state: Colorado
city: New Haven
country: United States
facility: Yale University
state: Connecticut
city: Washington
country: United States
facility: Children's National Medical Center
state: District of Columbia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Egleston
state: Georgia
city: Chicago
country: United States
facility: Lurie Children's Hospital-Chicago
state: Illinois
city: Indianapolis
country: United States
facility: Riley Hospital for Children
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins University/Sidney Kimmel Cancer Center
state: Maryland
city: Boston
country: United States
facility: Dana-Farber Cancer Institute
state: Massachusetts
city: Ann Arbor
country: United States
facility: C S Mott Children's Hospital
state: Michigan
city: Minneapolis
country: United States
facility: University of Minnesota/Masonic Cancer Center
state: Minnesota
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: New York
country: United States
facility: NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Children's Hospital of Pittsburgh of UPMC
state: Pennsylvania
city: Memphis
country: United States
facility: Saint Jude Children's Research Hospital
state: Tennessee
city: Houston
country: United States
facility: Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center
state: Texas
city: San Antonio
country: United States
facility: University of Texas Health Science Center at San Antonio
state: Texas
city: Norfolk
country: United States
facility: Children's Hospital of The King's Daughters
state: Virginia
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
Study officials:
affiliation: COG Phase I Consortium
name: Emily G Greengard
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.