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

To complete the form electronically, use the mouse pointer or the Tab key to navigate. Select and enter text for each text field. To complete the form manually, use the Letter of Intent form Acrobat (.pdf) format available from the CTEP Forms page at http://ctep.info.nih.gov/InfoForms/default.htm

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.

Laboratory corelates:

  • Pharmacokinetics
Bioanalytical assay
Exact bioanalytical conditions for SJG-136 have not yet been reported in the literature. DSB-120, a close analog to SJG-136, has been analyzed using HPLC with fluorescence detection (detection limit of 0.03 µg/ml, equivalent to 50 nM (Walton et al; 1996). Considering the potent pharmacological effect of SJG-136 at subnanomolar concentrations, it will be crucial to develop a sensitive bioanalytical assay. Using the expertise available at Vanderbilt University Mass Spectrometry Research Center, we will develop a sensitive bioanalytical assay via liquid chromatography/mass spectrometry (LC/MS). For benzodiazepine analogs, detection limits of ~ 1 ng/ml are routinely achieved by tandem LC/MS for the analysis of the parent drug. Analytical conditions for benzodiazepine analogs and their metabolites in biological samples have been previously established with detection limits of ~ 50 pg/ml or lower at Vanderbilt University Mass Spectrometry Research Center (Wandel et al; 2000). SJG-136 was reported to undergo minimal metabolism. However, the fact that SJG-136 concentration fell to 75% and 50% of the initial concentration after 48 hours incubation at 4°C and 37°C, respectively suggests degradation and/or metabolism of the parent compound that was not detected by HPLC with fluorescence detection. Analytical tools such as tandem LC/MS will allow us to identify additional products formed via degradation/metabolism in biological samples and also to monitor the levels of SJG-136 in plasma or tumor tissue samples.
Pharmacokinetics
The pharmacokinetic data in preclinical studies suggest that SJG-136 undergoes minimal metabolism and any metabolites are eliminated through the kidney. With a sensitive bioanalytical assay, we will be able to measure the levels of SJG-136 in plasma, urine and tumor biopsy samples. Pharmacokinetic analysis of SJG-136 and its metabolites will be performed to assess the disposition of SJG-136, dose linearity and schedule dependency using noncompartmental methods. In selected patients in whom we can acquire biopsy samples safely, tumor biopsy samples will be obtained prior to therapy and after 3 (or 5) days of treatment to measure the levels of SJG-136 and its metabolites. The presence of any correlation between tissue levels of SJG-136 and molecular/genetic markers will be further examined by either pharmacokinetic/pharmacodynamic modeling or correlation analysis.
  • Correlative studies (molecular/genetic markers)
Measurement of DNA and/or protein adduct formation in peripheral blood mononuclear cells and tumor tissue biopsy samples
The detection and quantification of DNA adducts is often analytically challenging as extremely high sensitivity and selectivity are required (de Kok et al: 2002). We will attempt to measure the formation of DNA and/or protein adducts by SJG-136 in tumor biopsy samples, as well as peripheral blood mononuclear cells using mass spectrometry or other relevant methods (Koc et al; 2002; Smellie et al; 1994). Using the expertise available at Vanderbilt University Mass Spectrometry Research Center, we will test mass spectrometric methods for the analysis of DNA and/or protein adducts formed by SJG-136, using approaches described in a recent paper by Liu et al. In this study, mutagenic DNA adduct formation by 1,2-dibromomethane, a DNA-alkylating agent was characterized using mass spectrometry at Vanderbilt University Mass Spectrometry Research Center (Liu et al: 2003). In addition, we will try different methods including sample preparation procedures as well as make comparisons in adduct formation between tumor samples and peripheral blood mononuclear cells (PBMC) which are readily available. The adduct formation in PBMCs might correlate with both beneficial and toxic drug effects.
Gene expression profiling
Gene expression patterns will be initially assessed with tumor biopsy samples from selected patients in whom tissue biopsy samples can be acquired safely, both pre-therapy and at selected time(s) during drug treatment. Using gene microarrays, we will probe various target genes differentially regulated by SJG-136.

In vitro treatment of LS174T human colon tumor cells has already shown that a number of genes related to DNA repair (e.g. RECA, XRCC1) were up-regulated following the exposure to SJG-136. Using the expertise available from Vanderbilt Microarray Shared Resource, we will assess the expression of various genes involved in tumorigenesis and drug resistance. We will compare the expression pattern of genes involved in DNA repair, in particular, those associated with resistance to DNA alkylating agents (for example, see table below). Gene expression patterns will also be compared between the patient subgroups depending on the responses to SJG-136 (e.g. tolerance, toxicity). In cases that a significant correlation exists between the expression levels of particular genes and SJG-136 responses, further studies will be carried out to verify the findings from gene microarray (e.g. quantitative real-time RT-PCR).

Table. DNA repair mechanisms and representative genes
Representative Genes  
Mismatch repair (MMR) MSH2
PMS1/2
MLH1
Associated with resistance to cisplatin [7, 8],
DNA minor groove binders (tallimustine, CC1065) [9]
Base excision repair (BER) MPG
OGG1
 
Nucleotide excision repair (NER) ERCC1/2*
XRCC
XPA
Associated with resistance to
cisplatin [10], oxaliplatin [11]
Direct damage reversal ATM
p53
 
DNA double-strand break (DSB) repair PARP
RAD
 
* functional polymorphisms identified

Protein will also be collected for Proteomic analysis by the Vanderbilt-Ingram Cancer Center Proteomics Shared Resource.

Genetic polymorphisms and Pharmacogenetics
The potential impact of functional genetic polymorphisms will be examined via individual genotyping using genomic DNA samples isolated from patient blood samples. For example, overexpression of excision repair cross-complementing (ERCC1) gene and other NER enzymes has been related to clinical resistance to cisplatin (Britten et al; 2000) and oxaliplatin (Shirota et al: 2001). A common polymorphism in the ERCC1 gene (C>T, exon 4) was recently reported to be associated with ERCC1 expression levels (Iqbal et al; 2003). We will examine the impact of genetic polymorphisms in ERCC1 or other DNA repair genes on the expression levels of such target genes and the clinical responses to SJG-136.

References:

  1. Walton MI, Goddard P, Kelland LR et al. Preclinical pharmacology and antitumour activity of the novel sequence-selective DNA minor-groove cross-linking agent DSB-120. Cancer Chemother Pharmacol 1996;38:431-438.
  2. Wandel C, Witte JS, Hall JM et al. CYP3A activity in African American and European American men: population differences and functional effect of the CYP3A4*1B5'-promoter region polymorphism. Clin Pharmacol Ther 2000;68:82-91.
  3. de Kok TM, Moonen HJ, van Delft J et al. Methodologies for bulky DNA adduct analysis and biomonitoring of environmental and occupational exposures. J Chromatogr B Analyt Technol Biomed Life Sci 2002;778:345-355.
  4. Koc H, Swenberg JA. Applications of mass spectrometry for quantitation of DNA adducts. J Chromatogr B Analyt Technol Biomed Life Sci 2002;778:323-343.
  5. Smellie M, Kelland LR, Thurston DE et al. Cellular pharmacology of novel C8-linked anthramycin-based sequence-selective DNA minor groove cross-linking agents. Br J Cancer 1994;70:48-53.
  6. Liu L, Hachey DL, Valadez G et al. Characterization of a mutagenic DNA adduct formed from 1,2-dibromoethane by O6-alkylguanine-DNA alkyltransferase. J Biol Chem 2003.
  7. Aebi S, Kurdi-Haidar B, Gordon R et al. Loss of DNA mismatch repair in acquired resistance to cisplatin. Cancer Res 1996;56:3087-3090.
  8. Drummond JT, Anthoney A, Brown R et al. Cisplatin and adriamycin resistance are associated with MutLalpha and mismatch repair deficiency in an ovarian tumor cell line. J Biol Chem 1996;271:19645-19648.
  9. Colella G, Marchini S, D'Incalci M et al. Mismatch repair deficiency is associated with resistance to DNA minor groove alkylating agents. Br J Cancer 1999; 80:338-343.
  10. Britten RA, Liu D, Tessier A et al. ERCC1 expression as a molecular marker of cisplatin resistance in human cervical tumor cells. Int J Cancer 2000;89:453-457.
  11. Shirota Y, Stoehlmacher J, Brabender J et al. ERCC1 and thymidylate synthase mRNA levels predict survival for colorectal cancer patients receiving combination oxaliplatin and fluorouracil chemotherapy. J Clin Oncol 2001; 19:4298-4304.
  12. Iqbal S, Lenz HJ. Targeted therapy and pharmacogenomic programs. Cancer 2003;97:2076-2082

Endpoints/Statistical Considerations:

  • Primary endpoints:
Since this is a Phase I study, the primary objectives relate to assessing the safety, toxicity, and pharmacokinetics of SJG-136
  1. Identification of the dose-limiting toxicities of SJG-136 when administered on a daily dosing schedule (qd x 3, qd x 5)
  2. Estimation of the maximum tolerated dose (MTD)/recommended Phase II dose (RPTD)
  3. Pharmacokinetic analysis of SJG-136 and its metabolites
  • Secondary endpoints:
  1. Measurement of drug-protein and drug-DNA adduct formation in peripheral blood mononuclear cells and, when available, post-treatment tumor biopsy samples. Exploratory analysis will be performed to identify any correlation between these and with observed clinical endpoints/toxicity
  2. Characterization of DNA repair gene expression patterns in tumor biopsies obtained pre- and post-treatment in patients enrolled in this study and exploration of potential correlations with toxicity and clinical response
  3. Pharmacogenetic analysis to identify polymorphisms in DNA repair genes and potential associations with pharmacokinetics, drug-protein or drug-DNA adduct formation, and clinical outcome
  • Statistical Considerations:
For cohorts of 3 patients, the probability of detecting Dose Limiting Toxicities in this study are as follows:

Number of DLTs in a cohort of 3 pts Incidence of DLTs in Patient Population
  0.10 0.20 0.30 0.40 0.50
0 0.729 0.512 0.343 0.216 0.125
1 0.243 0.384 0.441 0.432 0.375
2 or more 0.028 0.104 0.216 0.352 0.500

Categorical data will be summarized using frequency tables. Categorical modeling techniques may be used to explore the relationship of a bivariate response variable (tumor response) with a mixture of continuous and categorical prognostic variables.

Pharmacodynamic modeling will be performed to identify correlations between pharmacokinetic parameters and clinical outcomes. Due to the Phase I nature of this study, any laboratory-clinical correlational analysis must be considered to be exploratory and hypothesis-generating. Data will be plotted by dose group and appropriate parametric and nonparametric models will be generated to estimate the strength of association between the selected measures.

Estimated monthly accrual:

  • 2-4 patients

Proposed sample size:

  • 15-30 patients

Earliest date study can begin:

  • Upon CTEP approval

Projected Accrual Dates: (Month/Year format)

Start: ~03/2004 End: ~03/2005

To document accrual rate, list trials with patients who had similar tumor type/PS/prior Rx:

Trial Number Accrual Rate (number of patients/study duration)
VICC Phase I Trials 70-80 patients recruited per year with current waiting list of over 10 patients

List all active studies at your institution for which this patient population will be eligible.

  • Approximately 8-10 actively recruiting Phase I trials are opened at VICC at any given time. However, this trial will be given highest priority due to U01 support.

Is this LOI part of an NIH Grant, Cooperative Agreement or Contract?

  • Yes. UO1 CA099177-02 (to cover PK and clinical data accrual).

Are you receiving support from non-NCI sources (i.e., industry, ACS) for this study?

  • We plan to request Translational Research Initiative funding for gene array and pharmacogenetic studies. See separate budget proposal.

Principal Investigator (PI) Name: (Printed)

  • Mace L. Rothenberg, MD

PI Signature:

                                        Date: December 29, 2003

PI Street Address:

Vanderbilt-Ingram Cancer Center
777 Preston Research Building
Nashville, TN 37232-6307

PI Phone:

  • 615-936-3831

PI Fax:

  • 615-343-7602

PI E-mail:

Group Chair/Cooperative Agreement-PI (GCCA-PI) Name: (Printed)

  • NA

GCCA-PI Signature:

                                        Date:                    

GCCA-PI Address:

GCCA-PI Phone:

GCCA-PI Fax:

GCCA-PI E-mail:


LOIs can be submitted to the Protocol & Information Office electronically, Attn: LOI Coordinator at:

E-mail: pio@ctep.nci.nih.gov

Note: Cooperative group LOIs must be submitted through the group operations. Proposal for trials that will be conducted under cooperative agreement full information must be complete (Principle Investigator and Protocol Chair).

Questions? Please call LOI Coordinator at (301) 496-1367.
Topic revision: r6 - 13 Feb 2007, HeatherBurgess
 

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