A Phase I Trial of Daily Intravenous SJG-136 in Patients with Advanced Solid Tumors

Collaborators

Lynn.Matrisian@Vanderbilt.edu, Mace.Rothenberg@Vanderbilt.edu, David.Johnson@Vanderbilt.edu, Hal.Moses@Vanderbilt.edu, dougliles@earthlink.net, carlos.arteaga@vanderbilt.edu, david.carbone@vanderbilt.edu

LETTER OF INTENT	INVESTIGATIONAL DRUG TRIAL
National Cancer Institute Division of Cancer Treatment and Diagnosis Cancer Therapy

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Group/Institution(s):

• Vanderbilt Ingram Cancer Center

Title:

• A Phase I Trial of Daily Intravenous SJG-136 in Patients with Advanced Solid Tumors.

Agent to be supplied by NCI:

• SJG-136

Other agents supplied by NCI:

• None

Other agents:

• None

Tumor type:

• Phase I, II, or I/II Studies (check one below)
  • X Solid Tumor
  • Hematologic Malignancy (NOS)
  • Disease-Specific

Disease Specific:

• Specify the Name and Code of the Study Disease Below:

DISEASE NAME:	DISEASE CODE:

Performance status:

• 0-2

Abnormal organ function permitted:

• Yes
• Absolute neutrophil count (ANC>1,500)
• Platelet count>100,000
• Creatinine<1.5 x IUL
• Transaminases<2.5 x IUL, except for liver metastasis, when <5 x IUL would be permitted

Prior therapy:

• Any.
• Radiation therapy to < 25% of hematopoietic bone marrow

Phase of study:

• I

Treatment plan:

We will explore a daily dosing schedule in this Phase I clinical trial. Initially, SJG-136 will be administered on a daily x 3 basis. Patients will receive 20-minute intravenous infusion of 6.7 µg/m2/day SJG-136 daily on 3 consecutive days, every 3 weeks. This dose was determined by taking the dose recommended for the daily x 5 schedule and adjusting for a daily x 3 schedule to keep the total amount of drug delivered equal on a per cycle basis. Dose escalation will be performed using a modification of the accelerated dose titration method for Phase I trials (Simon et al; 1997). We will enroll a single patient per dose level at the beginning of the trial and observe that patient for DLT throughout the first cycle of therapy. Dose escalation increments will be determined by the toxicity observed in the previous dose level according to the following table:

Toxicity	% Increase Over Preceding Dose
No or minimal (CTC AE Grade 1)	50-100%
CTC AE Grade 2	31-49%
CTC AE Grade 3-4 (not qualifying as DLT)	10-30%

We feel that the flexibility afforded by this design is important because not all toxicities of a given grade have an equal effect upon the patient. Should a patient experience a Grade 2 or worse drug-induced toxicity, that, and all subsequent cohorts, will be expanded to 3-6 patients each and the dose escalation steps will be adjusted according to the table above. Once DLTs are defined and MTD is reached using daily x 3 schedule, we will decrease the individual daily dose by 40% and administer this dose on a daily x 5 schedule to achieve the same total dose over 5 day period. Three patients will be treated per cohort and further dose escalation will proceed as described above until the MTD is defined for the daily x 5 schedule. There are two main reasons for proposing this trial design: 1) physician and patient dissatisfaction with the inconvenience of daily x 5 dosing and 2) logistical difficulties that a daily x 5 dosing schedule poses for patients who live beyond close proximity to the medical center. However, if the daily x 3 dosing option is unacceptable to CTEP, we are willing to perform this Phase I trial using a daily x 5 schedule from the very beginning.

References:

Simon, R, Freidlin, B, Rubinstein, L, Arbuck, SG, Collins, J, Christian, MC. Accelerated titration designs for Phase I trials in oncology. J Natl Cancer Inst, 1997, 89 (15): 1138-47.

Rationale/Hypothesis:

SJG-136 is a rationally designed sequence-selective DNA cross-linking agent based on naturally occurring DNA-interactive antitumor antibiotics found in various Streptomyces species. Chemically, SJG-136 is a pyrrolobenzodiazepine dimer (PBD) that targets specific six-bp sequences of the pattern Pu-GATC-Py, creating sequence-specific crosslinks (Gregson et al., 2000). Recently, interest in agents that target precise DNA sequences has increased, due to the potential effects that these small molecules may have on altering transcription of specific genes. PBDs elicit antitumor effects by forming DNA crosslinks, interfering with endonuclease-DNA interactions, and inhibiting RNA polymerase (Puvvada et al., 1993; Puvvada et al., 1997). SJG-136 has demonstrated broad-spectrum activity at extremely low concentrations in a range of human tumor xenograft models and has a distinctive mechanism of action compared to other DNA-interactive agents.

Preliminary data also suggest that SJG-136-DNA adducts are resistant to repair, compared to adducts of other DNA-interactive agents. Finally, in initial toxicity studies, SGJ-136 displayed neither the cardiovascular effects of the structurally related anthramycins nor the discrepancy between human and murine bone marrow sensitivity of bizelesin. However, SJG-136 has not been carefully examined in terms of its disposition in humans, in particular tumor tissues.

We hypothesize that the levels of SJG-136- and/or DNA/protein adducts in tumor tissues may correlate with clinical responses to SJG-136. In addition, altered gene expression and/or genetic polymorphisms (in particular genes involved in DNA repair mechanisms) may have a significant impact on the response to SJG-136.

In order to glean as much information as possible, we propose four types of laboratory correlative studies to be performed as part of this Phase I trial:

1. Due to the potent biological effects of SJG-136, we will use LC/MS to develop a more sensitive pharmacological assay with detection limits of 1 ng/ml. This will also allow us to identify products formed by degradation and/or metabolism of SJG-136 in biological samples that may not be detectable using HPLC with fluorescence detection.
2. Since SJG-136 is thought to induce its cytotoxic effect via formation of DNA (and potentially, protein) crosslinks, we will obtain peripheral blood mononuclear cells and, whenever possible, pre- and post-treatment tumor biopsies and quantitate adduct formation using spectrometric methods.
3. Given the DNA-damaging effect of SJG-136, we will perform gene array analysis on tumor biopsies with a focus on those genes involved in DNA damage repair as well as those that might be differentially regulated by SJG-136,
4. We will extract DNA from PBMCs to characterize genetic polymorphisms that might influence the response to or toxicity from SJG-136, with a focus on genes likely to be involved in the metabolism, transport, and detoxification of the drug as well as in DNA repair genes.

Through the incorporation of these correlational studies, described in more detail below, we hope to make this Phase I trial as informative as possible in directing further clinical development of SJG-136.

References:

Gregson, S.J., P.W. Howard, J.A. Hartley, et al. (2001). Design, synthesis, and evaluation of a novel pyrrolobenzodiazepine DNA-interactive agent with highly efficient cross-linking ability and potent cytotoxicity. J Med Chem. 44:737-748.

Puvvada, M.S., J.A. Hartley, T.C. Jenkins, and D.E. Thurston. (1993). A quantitative assay to measure the relative DNA-binding affinity of pyrrolo [2,1-c] [1,4]benzodiazepine (PBD) antitumour antibiotics based on the inhibition of restriction endonuclease BamHI. Nucleic Acids Res. 21:3671-3675

Puvvada, M.S., S.A. Forrow, J.A. Hartley, et al. (1997). Inhibition of bacteriophage T7 RNA polymerase in vitro transcription by DNA-binding pyrrolo[2,1-c][1,4]benzodiazepines. Biochemistry. 36:2478-2484.