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

PHASE1PHASE2RECRUITING

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.

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Study details:

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. Patients also undergo bone marrow aspirate and/or biopsy at baseline, echocardiograph (ECHO) prior to cycle 1, and as clinically indicated undergo collection of blood samples throughout the trial. After completion of study treatment, patients are followed up at 3, 6, 9, 12, 18, 24, 36, 48 and 60 months.

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Eligibility criteria

Researchers look for people who fit a certain description, called eligibility criteria. See if you qualify.

Inclusion criteria

Patients must be >= 12 months and <= 21 years of age at the time of study enrollment in Parts A and B1.

Patients must be >= 12 months and <= 30 years of age at the time of study enrollment in Part B2 (relapsed/refractory osteosarcoma).

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.

Patients must have either measurable or evaluable disease in Part A.

Patients must have measurable disease in Parts B1 and B2.

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.

Cytotoxic chemotherapy or other anti-cancer agents known to be myelosuppressive: >= 21 days after the last dose of myelosuppressive chemotherapy (42 days if prior nitrosourea).

Anti-cancer agents not known to be myelosuppressive: >= 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.

Interleukins, interferons and cytokines (other than hematopoietic growth factors): >= 21 days after the completion of interleukins, interferon or cytokines.

Stem cell Infusions: Allogeneic 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.

Radiation therapy 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 radiation.

Radiopharmaceutical therapy: >= 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).

For patients with solid tumors without known bone marrow involvement: Platelet count >= 100,000/uL (transfusion independent) (performed within 7 days prior to enrollment unless otherwise indicated).

Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73 m^2 or a creatinine based on age/gender as specified.

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).

Serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) <= 135 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.

Nervous system disorders resulting from prior therapy must be <= grade 2, with the exception of decreased tendon reflex (DTR), where any grade of DTR is eligible.

Patients have consented to receive a central venous catheter prior to the administration of CBL0137.

Exclusion criteria

Pregnant or breast-feeding women will not be entered on this study due to risks of fetal and teratogenic adverse events.

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.

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 and CYP1A2 are not eligible.

Patients who are receiving drugs associated with a known risk of Torsades de Pointes (TdP) are not eligible.

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.

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Eligibility

Age eligible for study : 12 and older

Healthy volunteers accepted : No

Gender eligible for study: All

Things to know

Study dates

Study start: 2022-01-28

Primary completion: 2026-12-31

Study completion finish: 2026-12-31

Study type

TREATMENT

Phase

PHASE1

PHASE2

Trial ID

NCT04870944

Intervention or treatment

PROCEDURE: Biospecimen Collection

PROCEDURE: Bone Marrow Aspirate

PROCEDURE: Bone Marrow Biopsy

PROCEDURE: Echocardiography

DRUG: FACT Complex-targeting Curaxin CBL0137

Conditions

• Diffuse Midline Glioma, H3 K27M-Mutant
• Recurrent Malignant Solid Neoplasm
• Recurrent Osteosarcoma
• Refractory Malignant Solid Neoplasm
• Refractory Osteosarcoma
• Metastatic Malignant Neoplasm in the Central Nervous System
• Recurrent Diffuse Intrinsic Pontine Glioma
• Recurrent Lymphoma
• Recurrent Primary Malignant Central Nervous System Neoplasm
• Refractory Lymphoma
• Refractory Primary Malignant Central Nervous System Neoplasm

Image related to Diffuse Midline Glioma, H3 K27M-Mutant

Condition: Diffuse Midline Glioma, H3 K27M-Mutant, Recurrent Malignant Solid Neoplasm and more
PROCEDURE: Biospecimen Collection and other drugs
Randwick, New South Wales, Australia
Sponsor: Children's Oncology Group

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Find a site

Closest Location:

Sydney Children's Hospital

Research sites nearby

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Sydney Children's Hospital
Randwick, New South Wales, Australia

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Participant Group/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. Patients also undergo bone marrow aspirate and/or biopsy at baseline, ECHO prior to cycle 1, and as clinically indicated undergo collection of blood samples throughout the trial.	PROCEDURE: Biospecimen Collection Undergo collection of blood samples

What is the study measuring?

Primary outcome

Primary Outcome Measure	Primary Outcome Description	Primary Outcome Time Frame
Maximum tolerated dose and/or Recommended Phase 2 dose of CBL0137	Maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of CBL0137 in children with relapsed or refractory solid tumors including CNS tumors and lymphoma.	Up to 21 days
Frequency of dose limiting toxicities of CBL0137 (Phase I)	The frequency (%) of patients experiencing a cycle 1 dose limiting toxicity attributable to CBL0137 by study part and dose level.	Up to 21 days
Anti-tumor effect of CBL0137 in children with diffuse intrinsic pontine glioma (DIPG) or other H3 K27M-mutant diffuse midline gliomas (Phase II)	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).	Up to 4 months
Anti-tumor effect of CBL0137 in children with osteosarcomas (Phase II)	Frequency (%) of patients with complete response, partial response, or stable disease for at least 4 months to CBL0137 at the MTD/RP2D in children with Osteosarcoma.	Up to 4 months

Secondary outcome

Secondary Outcome Measure	Secondary Outcome Description	Secondary Outcome Time Frame
Anti-tumor effect of CBL0137 in children with solid tumors (Phase I)	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.	Up to 4 months
Frequency of adverse events attributable to CBL0137	The frequency (%) of patients experiencing adverse events that are at least possibly attributable to CBL0137 by study part and dose level.	Up to 60 months
Area under the drug concentration curve of CBL0137	The median (min, max) of the area under the drug concentration curve for CBL0137 by study part and dose level.	Up to 3 days

Frequently Asked Questions

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References

Clinical Trials Gov: CBL0137 for the Treatment of Relapsed or Refractory Solid Tumors, Including CNS Tumors and Lymphoma