CBL0137 for the Treatment of Relapsed or Refractory Solid Tumors, Including CNS Tumors and Lymphoma

• ClinicalTrials.gov Identifier: NCT04870944
• Recruitment Status: Active, not recruiting
• First Posted: May 4, 2021
• Last Update Posted: July 5, 2022
• Sponsor: Children's Oncology Group
• Collaborator: Incuron LLC
• Information provided by (Responsible Party): Children's Oncology Group

Study Description

Brief Summary:

This phase I/II trial evaluates the best dose, side effects and possible benefit of CBL0137 in treating patients with solid tumors, including central nervous system (CNS) tumors or lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Drugs, such as CBL0137, block signals passed from one molecule to another inside a cell. Blocking these signals can affect many functions of the cell, including cell division and cell death, and may kill cancer cells.

Condition or disease	Intervention/treatment	Phase
Diffuse Midline Glioma, H3 K27M-Mutant; Metastatic Malignant Neoplasm in the Central Nervous System; Recurrent Diffuse Intrinsic Pontine Glioma; Recurrent Lymphoma; Recurrent Malignant Solid Neoplasm; Recurrent Osteosarcoma; Recurrent Primary Malignant Central Nervous System Neoplasm; Refractory Lymphoma; Refractory Malignant Solid Neoplasm; Refractory Osteosarcoma; Refractory Primary Malignant Central Nervous System Neoplasm	Drug: FACT Complex-targeting Curaxin CBL0137	Phase 1; Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To estimate the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of FACT complex-targeting curaxin CBL0137 (CBL0137) administered via infusion on Day 1 and Day 8 of a 21-day cycle to children with recurrent or refractory solid tumors, including CNS tumors and lymphoma. (Phase 1 Dose Escalation) II. To preliminarily determine the antitumor effects as measured by objective response rate of CBL0137 in children with progressive/recurrent diffuse intrinsic pontine glioma (DIPG) and other H3 K27M-mutant diffuse midline gliomas. (Phase 2) III. To preliminarily determine the antitumor effects as measured by objective response rate or stable disease for at least 4 months of CBL0137 in children, adolescents and young adults with osteosarcoma. (Phase 2)

SECONDARY OBJECTIVES:

I. To preliminarily determine the antitumor effects of CBL0137 in children with refractory solid tumors and other CNS tumors, to the extent possible in the context of a Phase 1 study.

II. To define and describe the toxicities of CBL0137 in children with recurrent or refractory solid tumors, including CNS tumors.

III. To characterize the pharmacokinetics of CBL0137 in children with recurrent or refractory solid tumors, including CNS tumors.

EXPLORATORY OBJECTIVES:

I. To measure biologic marker FACT in tumor specimens with potential for correlation with disease response.

II. To evaluate the effect of CBL0137 on immune response by measuring the effects on the interferon response pathway in peripheral blood mononuclear cells.

III. To preliminarily determine the effect of treatment with CBL0137 on overall survival of children with DIPG or other diffuse midline gliomas, H3 K27M-mutant, in comparison with historical controls.

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

Patients receive CBL0137 intravenously (IV) over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 36, 48 and 60 months.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 38 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1/2 Trial of CBL0137 (NSC# 825802) in Patients With Relapsed or Refractory Solid Tumors, Including CNS Tumors and Lymphoma
• Actual Study Start Date: January 18, 2022
• Estimated Primary Completion Date: December 31, 2026
• Estimated Study Completion Date: December 31, 2026

Arms and Interventions

Arm	Intervention/treatment
Experimental: Treatment (CBL0137); Patients receive CBL0137 IV over 30 minutes on days 1 and 8. Treatment repeats every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.	Drug: FACT Complex-targeting Curaxin CBL0137; Given IV; Other Name: CBL0137

Outcome Measures

Primary Outcome Measures :

1. Frequency of dose limiting toxicities of CBL0137 (Phase I) [ Time Frame: Up to 21 days ]
   The frequency (%) of patients experiencing a dose limiting toxicity attributable to CBL0137 by study part and dose level.
2. Anti-tumor effect of CBL0137 in children with diffuse intrinsic pontine glioma (DIPG) or other H3 K27M-mutant diffuse midline gliomas (Phase II) [ Time Frame: Up to 4 months ]
   Frequency (%) of patients with at least partial response to CBL0137 at the maximum tolerated dose/recommended phase II dose (MTD/RP2D) in children with progressive or recurrent diffuse intrinsic pontine glioma (DIPG).
3. Anti-tumor effect of CBL0137 in children with osteosarcomas (Phase II) [ Time Frame: Up to 4 months ]
   Frequency (%) of patients with at least partial response to CBL0137 at the MTD/RP2D in children with Osteosarcoma.

Secondary Outcome Measures :

1. Anti-tumor effect of CBL0137 in children with solid tumors (Phase I) [ Time Frame: Up to 4 months ]
   Frequency (%) of patients with at least partial response to CBL0137 at the MTD/RP2D in children with refractory solid tumors and other central nervous system (CNS) tumors.
2. Frequency of adverse events attributable to CBL0137 [ Time Frame: Up to 60 months ]
   The frequency (%) of patients experiencing adverse events that are at least possibly attributable to CBL0137 by study part and dose level.
3. Area under the drug concentration curve of CBL0137 [ Time Frame: Up to 1 day ]
   The median (min, max) of the area under the drug concentration curve for CBL0137 by study part and dose level.
4. Maximum serum concentration of CBL0137 [ Time Frame: Up to 1 day ]
   Median (min, max) of the maximum serum concentration of CBL0137 by study part dose level.
5. Minimum serum concentration of CBL0137 [ Time Frame: Up to 1 day ]
   Median (min, max) of the minimum serum concentration of CBL0137 by study part and dose level.
6. Clearance of CBL0137 [ Time Frame: Up to 1 day ]
   Median (min, max) of the clearance of CBL0137 by study part and dose level.
7. Half-life of CBL0137 [ Time Frame: Up to 1 day ]
   Median (min, max) of the half-life of CLB0137 by study part and dose level.

Other Outcome Measures:

1. FACT in tumor specimens [ Time Frame: Up to 60 months ]
   A descriptive analysis of biomarkers will assess associations with disease response. The parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). All these analyses will be descriptive and exploratory and hypotheses generating in nature. FACT expression in tumor specimens will be determined by immunohistochemistry.
2. Immune response [ Time Frame: Up to 60 months ]
   Will measure effects on the interferon response pathway. A descriptive analysis of biomarkers will assess associations with disease response. The parameters will be summarized with simple summary statistics, including means, medians, ranges, and standard deviations (if numbers and distribution permit). All these analyses will be descriptive and exploratory and hypotheses generating in nature. Peripheral blood lymphocytes will be assessed for expression of genes in the interferon response pathway, in order to determine whether treatment with CBL0137 leads to increase gene expression.
3. Overall survival [ Time Frame: Up to 60 months ]
   Will be compared with historical controls in children with DIPG or other diffuse midline gliomas, H3 K27M-mutant.
4. Progression-free survival [ Time Frame: Up to 60 months ]
   An exploratory analysis of progression-free survival using Kaplan-Meier curves and the log-rank test statistic will compare overall time-to-disease progression (or death) versus historical cohort for the DIPG cohort.

Eligibility Criteria

• Ages Eligible for Study: 12 Months to 30 Years (Child, Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

• Parts A and B1: Patients must be >= 12 months and =< 21 years of age at the time of study enrollment
• Part B2 (relapsed/refractory osteosarcoma): Patients must be >= 12 months and =< 30 years of age at the time of study enrollment

• Patients must have had histologic verification of malignancy at original diagnosis or relapse, except in patients with diffuse intrinsic brain stem tumors, or patients with pineal tumors and elevations of cerebrospinal fluid (CSF) or serum tumor markers, including alpha-fetoprotein or beta-human chorionic gonadotropin (HCG)

  • Part A: Patients with relapsed or refractory solid tumors or lymphoma, including patients with CNS tumors or known CNS metastases (including untreated or progressive) are eligible
  • Part B1: Patients with progressive or recurrent DIPG (diagnosed by biopsy or imaging characteristics) and other H3 K27M-mutant diffuse midline gliomas previously treated with radiation therapy
  • Part B2: Patients with relapsed or refractory osteosarcoma
• Part A: Patients must have either measurable or evaluable disease
• Part B1 and B2: 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
• Patients must have a performance status corresponding to Easter Cooperative Oncology Group (ECOG) scores of 0, 1 or 2. Use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age. Patients must have a Karnofsky or Lansky score >= 50%

• 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

    • Solid tumor patients: >= 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea)
  • Anti-cancer agents not known to be myelosuppressive (eg, 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. Patients with CNS tumors receiving corticosteroids must have been on a stable or decreasing dose of corticosteroid for at least 7 days prior to enrollment
  • 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
  • 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: >= 30 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, I-131 metaiodobenzylguanidine [131I MIBG]): >= 42 days after systemically administered radiopharmaceutical therapy
  • Patients must not have received prior exposure to CBL0137

• For patients with solid tumors without known bone marrow involvement:

  • Peripheral absolute neutrophil count (ANC) >= 1000/uL (performed within 7 days prior to enrollment unless otherwise indicated)
  • Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (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

• For patients with solid tumors without known bone marrow involvement:

  • Platelet count >= 100,000/uL (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment) (performed within 7 days prior to enrollment unless otherwise indicated)
  • Patients with known bone marrow metastatic disease will be eligible for study provided they meet the blood counts (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 creatinine based on age/gender as follows (performed within 7 days prior to enrollment unless otherwise indicated):

  • Age: Maximum serum creatinine (mg/dL)
  • 1 to < 2 years: 0.6 (male); 0.6 (female)
  • 2 to < 6 years: 0.8 (male); 0.8 (female)
  • 6 to < 10 years: 1 (male); 1 (female)
  • 10 to < 13 years: 1.2 (male); 1.2 (female)
  • 13 to < 16 years: 1.5 (male); 1.4 (female)
  • >= 16 years: 1.7 (male); 1.4 (female)

• Patients with solid tumors:

  • Bilirubin (sum of conjugated + unconjugated or total) =< 1.5 x upper limit of normal (ULN) for age (performed within 7 days prior to enrollment unless otherwise indicated)

• Patients with solid tumors:

  • Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 135 U/L. For the purpose of this study, the ULN for SGPT is 45 U/L (performed within 7 days prior to enrollment unless otherwise indicated)
• Shortening fraction of >= 27% by echocardiogram (performed within 7 days prior to enrollment unless otherwise indicated)
• Ejection fraction of >= 50% by gated radionuclide study (performed within 7 days prior to enrollment unless otherwise indicated)
• Corrected QT (QTC) < 480 msec (performed within 7 days prior to enrollment unless otherwise indicated)
• Patients with seizure disorder may be enrolled if seizures well controlled without the use of enzyme-inducing anti-convulsant agents. Well controlled is defined by no increase in seizure frequency in the prior 7 days
• Nervous system disorders (Common Terminology Criteria for Adverse Events [CTCAE] version [v]5) resulting from prior therapy must be =< grade 2, with the exception of decreased tendon reflex (DTR). Any grade of DTR is eligible
• Patients have consented to receive a central venous catheter prior to the administration of CBL0137. A central line is required for CBL0137 administration

Exclusion Criteria:

• Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events as seen in animal/human studies, OR because there is yet no available information regarding human fetal or teratogenic toxicities. 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 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 corticosteroid
• 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 are receiving drugs that are strong inducers or inhibitors of CYP3A4, CYP2B6 (e.g., carbamazepine) and CYP1A2 (e.g., ciprofloxacin, enoxacin, fluvoxamine, smoking) are not eligible. These agents are to be avoided for 7 days prior to the start of CBL0137 and for the duration of the protocol therapy. Sensitive substrates of CYP2D6 (e.g., atomoxetine, desipramine, dextromethorphan, eliglustat, nebivolol, nortriptyline, perphenazine, tolterodine, R-venlafaxine) should also be avoided for the duration protocol therapy
• Patients who are receiving drugs that prolong QTc are not eligible. QTc- prolonging drugs are to be avoided for 7 days prior to the start of CBL0137 and for duration of the protocol therapy
• Patients with known peripheral vascular disease are excluded
• Patients with a history of pro-thrombotic disorder are not eligible
• 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

Contacts and Locations

Locations

United States, Alabama

Children's Hospital of Alabama

Birmingham, Alabama, United States, 35233

United States, California

Children's Hospital Los Angeles

Los Angeles, California, United States, 90027

Children's Hospital of Orange County

Orange, California, United States, 92868

UCSF Medical Center-Mission Bay

San Francisco, California, United States, 94158

United States, District of Columbia

Children's National Medical Center

Washington, District of Columbia, United States, 20010

United States, Indiana

Riley Hospital for Children

Indianapolis, Indiana, United States, 46202

United States, Massachusetts

Dana-Farber Cancer Institute

Boston, Massachusetts, United States, 02215

United States, Michigan

C S Mott Children's Hospital

Ann Arbor, Michigan, United States, 48109

United States, Minnesota

University of Minnesota/Masonic Cancer Center

Minneapolis, Minnesota, United States, 55455

United States, Missouri

Children's Mercy Hospitals and Clinics

Kansas City, Missouri, United States, 64108

Washington University School of Medicine

Saint Louis, Missouri, United States, 63110

United States, New York

Roswell Park Cancer Institute

Buffalo, New York, United States, 14263

NYP/Columbia University Medical Center/Herbert Irving Comprehensive Cancer Center

New York, New York, United States, 10032

United States, Ohio

Cincinnati Children's Hospital Medical Center

Cincinnati, Ohio, United States, 45229

United States, Pennsylvania

Children's Hospital of Philadelphia

Philadelphia, Pennsylvania, United States, 19104

Children's Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, United States, 15224

United States, Tennessee

Saint Jude Children's Research Hospital

Memphis, Tennessee, United States, 38105

United States, Texas

Cook Children's Medical Center

Fort Worth, Texas, United States, 76104

Baylor College of Medicine/Dan L Duncan Comprehensive Cancer Center

Houston, Texas, United States, 77030

United States, Utah

Primary Children's Hospital

Salt Lake City, Utah, United States, 84113

Sponsors and Collaborators

Children's Oncology Group

Incuron LLC

Investigators

• Principal Investigator: David S Ziegler; Pediatric Early Phase Clinical Trial Network

More Information

• Responsible Party: Children's Oncology Group
• ClinicalTrials.gov Identifier: NCT04870944
• Other Study ID Numbers: PEPN2111; NCI-2021-03150 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) ); PEPN2111 ( Other Identifier: Pediatric Early Phase Clinical Trial Network ); PEPN2111 ( Other Identifier: CTEP ); UM1CA228823 ( U.S. NIH Grant/Contract )
• First Posted: May 4, 2021
• Last Update Posted: July 5, 2022
• Last Verified: June 2022

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

Additional relevant MeSH terms:

Lymphoma; Neoplasms; Glioma; Osteosarcoma; Diffuse Intrinsic Pontine Glioma; Central Nervous System Neoplasms; Nervous System Neoplasms; Recurrence; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Disease Attributes; Pathologic Processes; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Connective and Soft Tissue; Sarcoma; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases