A Phase I Study of Indenoisoquinolines LMP400 and LMP776 in Adults With Relapsed Solid Tumors and Lymphomas

This study is currently recruiting participants.
Verified October 2013 by National Institutes of Health Clinical Center (CC)
Sponsor:
Information provided by (Responsible Party):
National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier:
NCT01051635
First received: January 15, 2010
Last updated: March 14, 2014
Last verified: October 2013
  Purpose

Background:

  • Indenoisoquinolines are experimental cancer treatment drugs that damage the DNA in cells, resulting in cell death. Researchers have been studying these drugs and their usefulness in treating types of cancer that have not responded well to standard therapies like surgery or radiation.
  • LMP400 (NSC 743400) and LMP776 (NSC 725776) are indenoisoquinolines that have not been given to cancer patients before. These drugs have very similar chemical structures and work the same way, but researchers do not know which one will work best. More information is needed about how LMP400 and LMP776 are processed by the body and how effective they are in treating difficult-to-treat types of cancer.

Objectives:

  • To determine the maximum tolerated dose of LMP400 (NSC 743400) and LMP776 (NSC 725776).
  • To study how the body handles LMP400 and LMP776.
  • To evaluate the effectiveness of LMP400 and LMP776 as a treatment for tumors and lymphoma that have not responded to standard treatment.

Eligibility:

- Individuals at least 18 years of age who have malignant solid tumors or Hodgkin s disease/non-Hodgkin lymphoma that has not responded to standard therapies.

Design:

  • Participants will receive either LMP400 or LMP776. The treatment cycle will be 28 days. On the first 5 days of each cycle, participants will receive intravenous doses of their specific study drug, followed by 23 days without the drug. The 28-day cycle will be repeated as long as the drug does not cause severe side effects and the cancer remains stable or improves. The study doctor may increase or decrease the dose of study drug depending on how well it is tolerated.
  • Blood, urine, and hair samples and skin and tumor biopsies will be collected during the first treatment cycle. Routine blood samples will be taken throughout the study.
  • Other tests, including additional blood and urine samples, computed tomography (CT) or other scans, and bone marrow samples, may be performed as directed by the study doctors....

Condition Intervention Phase
Neoplasms
Lymphoma
Drug: LMP 400
Drug: LMP 776
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Parallel Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: A Phase I Study of Indenoisoquinolines LMP400 and LMP776 in Adults With Relapsed Solid Tumors and Lymphomas

Resource links provided by NLM:


Further study details as provided by National Institutes of Health Clinical Center (CC):

Primary Outcome Measures:
  • Define the MTD and DLTs of NSCs 743400 and 725776 administered IV daily for 5 days (QDx5) in patients with relapsed solid tumors and lymphomas. Compare the agents PD response at the MTD and the toxicity profile versus PD dose-response relationsh...

Secondary Outcome Measures:
  • Characterize the pharmacokinetic (PK) profile of NSCs 743400 and 725776.

Estimated Enrollment: 74
Study Start Date: January 2010
Intervention Details:
    Drug: LMP 400
    N/A
    Drug: LMP 776
    N/A
Detailed Description:

Background:

  • Indenoisoquinolines are non-camptothecin inhibitors of topoisomerase 1 (top1) with improved characteristics over their predecessors. Indenoisoquinolines have better chemical stability, producing stable DNA-top1 cleavage complexes, and exhibit a preference for unique DNA cleavage sites, compared with their camptothecin counterparts.
  • They have demonstrated activity against camptothecin-resistant cell lines and produce DNA-protein crosslinks, which are resistant to reversal. They also show less or no resistance to cells overexpressing the ATP-binding cassette (ABC) transporters, ABCG2, and multidrug resistance (MDR-1).

Primary Objectives:

  • Define the maximum tolerated dose (MTD) of LMP400 (NSC 743400) and LMP776 (NSC 725776) administered intravenously (IV) daily for 5 days (QDx5).
  • Define the dose-limiting toxicities (DLTs) and toxicity profile associated with administration of LMP400 and LMP776.
  • Evaluate the effect of LMP400 and LMP776 on the pharmacodynamic (PD) endpoint, gamma-H2AX, in tumor biopsy pre- and post-treatment. In particular, compare the PD response, defined as the mean percent nuclear area that is gamma-H2AX positive (%NAP) in tumor biopsies, at the MTD for LMP400 and LMP776, and the toxicity profile versus PD dose-response relationship.

Secondary Objectives:

  • Obtain preliminary evidence of anti-tumor activity of LMP400 and LMP776.
  • Characterize the pharmacokinetic (PK) profile of LMP400 and LMP776.

Eligibility:

-Adult patients must have histologically confirmed relapsed solid tumor malignancy or lymphoma that is metastatic or unresectable for which standard curative measures do not exist or are associated with minimal patient survival benefit.

Study Design:

  • Cycle 1 and subsequent cycles: Patients will be randomized to receive either LMP400 or LMP776 administered IV QD over 1 hour on days 1 5 followed by 23 days without drug (28-day cycle).
  • PK and PD samples will be collected in cycle 1 only. Tumor biopsies will be optional until a consistent PD response is observed in surrogate tissue skin biopsies or toxicity is encountered (one DLT or two Grade 2 events on the same dose level), at which point tumor biopsies will become mandatory.
  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria
  • INCLUSION CRITERIA:
  • Patients must have histologically documented (confirmed at the Laboratory of Pathology, NCI), relapsed solid tumor malignancy or Hodgkin s disease/non-Hodgkin lymphoma that is metastatic or unresectable for which standard curative measures do not exist, or are associated with minimal patient survival benefit.
  • Patients must have measurable or evaluable disease.
  • 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 chemotherapy or biologic therapy within 4 weeks (6 weeks for nitrosoureas and mitomycin C, or 2 months for UCN-01), or therapy with tyrosine kinase inhibitors within 5 times the half-life of the inhibitors prior to entering the study. Patients must be (Bullet)2 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 sub-therapeutic dose of drug is administered) at the PI s discretion, and should have recovered to eligibility levels from any toxicities. Patients must be (Bullet)1 month since completion of any prior radiation. 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.
  • Age greater than or equal to 18 years.
  • The Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).
  • Life expectancy greater than 3 months.
  • Patients must have normal or adequate organ and marrow function as defined below:

    • Absolute neutrophil count greater than or equal to 1,500/microL
    • Platelets greater than or equal to 100,000/microL
    • Total bilirubin* within less than or equal to 1.5 normal institutional limits
    • AST (SGOT)/ALT (SGPT) less than or equal to 2.5 times institutional upper limit of normal
    • Creatinine less than 1.5 times upper limit of normal

OR

  • Creatinine clearance greater than or equal to 60 mL/minute for patients with (measured) creatinine levels greater than or equal to 1.5 times upper limit of normal

    • we will allow patients with Gilbert s syndrome with total bilirubin up to 2.5 mg/dL

      • The effects of indenoisoquinolines on the developing human fetus are unknown. For this reason, women of child-bearing potential and men must agree to use adequate contraception (hormonal or barrier method of birth control or abstinence) prior to study entry, for the duration of study participation, and for 2 months after discontinuation from the study. Women of child bearing potential must have a negative pregnancy test in order to be eligible. Should a woman become pregnant or suspect she is pregnant while participating in this study, she should inform her treating physician immediately. Because there is an unknown but potential risk to nursing infants secondary to treatment of the mother with indenoisoquinolines, breastfeeding should be discontinued if the mother is treated with indenoisoquinolines.
      • Willingness to undergo skin biopsies.
      • At the point when tumor biopsies become mandatory rather than optional, disease amenable to biopsy and willingness to undergo biopsies.
      • Ability to understand and the willingness to sign a written informed consent document.

EXCLUSION CRITERIA:

  • Patients receiving any other investigational agents.
  • Patients with known brain metastases are excluded from this clinical trial, with the exception of patients whose brain metastatic disease status has remained stable for greater than or equal to 2 months after treatment of the brain metastases, without steroids or anti-seizure medications. These patients may be enrolled at the discretion of the principal investigator.
  • Patients with clinically significant illnesses which could compromise participation in the study, including, but not limited to, active or uncontrolled infection, immune deficiencies, known HIV infection requiring antiretroviral therapy, Hepatitis B, Hepatitis C, uncontrolled diabetes, uncontrolled hypertension, symptomatic congestive heart failure, unstable angina pectoris, myocardial infarction within the past 6 months, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
  Contacts and Locations
Please refer to this study by its ClinicalTrials.gov identifier: NCT01051635

Contacts
Contact: Deborah E Allen, R.N. (301) 402-5640 allendeb@mail.nih.gov
Contact: Shivaani Kummar, M.D. (301) 435-0517 kummars@mail.nih.gov

Locations
United States, Maryland
National Institutes of Health Clinical Center, 9000 Rockville Pike Recruiting
Bethesda, Maryland, United States, 20892
Contact: For more information at the NIH Clinical Center contact National Cancer Institute Referral Office    (888) NCI-1937      
Sponsors and Collaborators
Investigators
Principal Investigator: Shivaani Kummar, M.D. National Cancer Institute (NCI)
  More Information

Additional Information:
Publications:
Responsible Party: National Institutes of Health Clinical Center (CC) ( National Cancer Institute (NCI) )
ClinicalTrials.gov Identifier: NCT01051635     History of Changes
Obsolete Identifiers: NCT01245192
Other Study ID Numbers: 100056, 10-C-0056
Study First Received: January 15, 2010
Last Updated: March 14, 2014
Health Authority: United States: Federal Government

Keywords provided by National Institutes of Health Clinical Center (CC):
DNA Repair
DNA Damage
Advanced Cancer
Advanced Malignancies
Topoisomerase Inhibitor

Additional relevant MeSH terms:
Neoplasms
Lymphoma
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Pharmacologic Actions
Antineoplastic Agents
Therapeutic Uses

ClinicalTrials.gov processed this record on April 21, 2014