Indenoisoquinoline LMP400 for Advanced Solid Tumors and Lymphomas

NCT01794104 | Completed Phase 1

• 2 other identifiers: 13008013-C-0080
• Study Type: interventional
• Target: 21
• Locations: 1 country
• Sites: 1

Brief Summary

Background: \- Indenoisoquinoline LMP400 is an experimental cancer treatment drug. It damages DNA in tumor cells. Tumor cells with damaged DNA may die, resulting in cell death. Researchers want to see if this drug is a safe and effective treatment for solid tumors and lymphomas that have not responded to earlier treatment. Objectives: \- To see if Indenoisoquinoline LMP400 is a safe and effective treatment for advanced solid tumors or lymphomas. Eligibility: \- Individuals at least 18 years of age who have solid tumors or lymphomas that have not responded to treatment. Design:

• Participants will be screened with a physical exam and medical history. Blood and urine samples will be collected. Tumor samples may also be collected. The size and location of the tumors will be determined with imaging studies.
• Indenoisoquinoline LMP400 is given in a 28-day cycle. Participants will receive the drug by intravenous infusion on days 1, 8, and 15 of each cycle, followed by a break of 13 days without the drug.
• Treatment will be monitored with frequent blood tests and imaging studies. Tumor samples will be optional.
• Participants will continue their cycles of treatment as long as the cancer does not grow and there are no severe side effects.

Conditions

Neoplasm; Lymphoma

Keywords

Topoisomerase Inhibitor; Advanced Malignancies; Pharmacodynamics; DNA Damage; Pharmacokinetics

Outcome Measures

Primary Outcomes (1)

• To establish the safety and tolerability of weekly (days 1, 8, 15 q28-day cycle) LMP400 in patients with refractory solid tumors and lymphomas

  Cycle 1

Secondary Outcomes (1)

• Evaluate the level of Top1 in tumor biopsies pre and post- administration of LMP400

  Cycle 1

Study Arms (1)

1

EXPERIMENTAL

Open-label Phase I trial evaluating weekly administration of LMP400, on days 1, 8, and 15, in 28-day cycles.

Drug: LMP400

Interventions

LMP400 DRUG

Top1 inhibitors such as LMP400 are potent anticancer agents because stabilizing cleavage complex formation induces replication-and transcription-mediated DNA damage and delays DNA repair, leading to apoptosis. Preclinical and clinical data indicate that baseline tumor levels of Top1 correlate strongly with ability to respond to Top1 inhibitor therapy.

1

Eligibility Criteria

• Age: 18 Years - 120 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must have histologically-documented (confirmed at the Laboratory of Pathology, NCI), solid tumor malignancy, or Hodgkin's disease/non-Hodgkin lymphoma, that is metastatic or unresectable and for which standard curative measures do not exist or are associated with minimal patient survival benefit.
• The Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
• Life expectancy \>3 months.
• Patients must have normal or adequate organ and marrow function as defined below:
• Leukocytes greater than or equal to 3,000/mcL
• Absolute neutrophil count greater than or equal to 1,500/microL
• Platelets greater than or equal to 100,000/microL
• Total bilirubin less than or equal to 2.0 x institutional upper limit of normal (we will allow patients with Gilbert s syndrome with total bilirubin up to 2.5 mg/dL)
• AST (SGOT)/ALT (SGPT) less than or equal to 3 x institutional upper limit of normal
• patients with metastatic disease in the liver less than or equal to 5 x ULN
• Creatinine \<1.5 x upper limit of normal
• Creatinine clearance
• greater than or equal to 60 mL/minute for patients with creatinine levels
• greater than or equal to 1.5 x institutional upper limit of normal
• Age greater than or equal to 18

You may not qualify if:

• Patients must have recovered to at least eligibility levels due to adverse events (AEs) and/or toxicity of prior chemotherapy or biologic therapy. They must not have had major surgery, chemotherapy, radiotherapy, or biologic therapy within 3 weeks (6 weeks for nitrosoureas and mitomycin C, or 2 months for UCN-01). Patients must be greater than or equal to2 weeks since any investigational agent administered as part of a Phase 0 study (also referred to as an early Phase I study or pre-Phase I study where a subtherapeutic dose of drug is administered) at the PI s discretion, and should have recovered to eligibility levels from any toxicities. However, patients receiving bisphosphonates for any cancer or undergoing androgen deprivation therapy for prostate cancer are eligible for this therapy. Prior therapy with topoisomerase I inhibitors is allowed.
• Patients who are receiving any other investigational agents.
• Patients with known active brain metastases are excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. Patients with brain metastasis stable for at least 4 weeks following surgery and/or radiation are eligible.
• Uncontrolled incurrent illness including, but not limited to, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with LMP400. Appropriate studies will be undertaken in patients receiving combination antiretroviral therapy when indicated.
• \- Both men and women of all races and ethnic groups are eligible for this trial.

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (4)

• Champoux JJ. DNA topoisomerases: structure, function, and mechanism. Annu Rev Biochem. 2001;70:369-413. doi: 10.1146/annurev.biochem.70.1.369.

  PMID: 11395412 BACKGROUND

• Wang JC. Cellular roles of DNA topoisomerases: a molecular perspective. Nat Rev Mol Cell Biol. 2002 Jun;3(6):430-40. doi: 10.1038/nrm831.

  PMID: 12042765 BACKGROUND

• Pommier Y. Topoisomerase I inhibitors: camptothecins and beyond. Nat Rev Cancer. 2006 Oct;6(10):789-802. doi: 10.1038/nrc1977.

  PMID: 16990856 BACKGROUND

• Beumer JH, Kennard BC, Holleran JL, Moore N, Zlott J, Miller BM, Kummar S, Chen A, Doroshow J, Park W, Gobburu J, Dunn A. Evaluating the indotecan-neutropenia relationship in patients with solid tumors by population pharmacokinetic modeling and sigmoidal Emax regressions. Cancer Chemother Pharmacol. 2023 Mar;91(3):219-230. doi: 10.1007/s00280-023-04509-8. Epub 2023 Feb 23.

  PMID: 36813886 DERIVED

MeSH Terms

Conditions

Neoplasms; Lymphoma

Interventions

NSC 724998

Condition Hierarchy (Ancestors)

Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Study Officials

• Alice P Chen, M.D.

  National Cancer Institute (NCI)

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: February 15, 2013
• First Posted: February 18, 2013
• Study Start: February 15, 2013
• Primary Completion: May 19, 2016
• Study Completion: October 27, 2017
• Last Updated: September 27, 2018

Record last verified: 2017-10-27

Locations

US (1)