TRC102 and Temozolomide for Relapsed Solid Tumors and Lymphomas
Condition: Lymphomas; Solid Tumors; NSCLC; Metastatic Colon Carcinoma; Granulosa Cell Ovarian Cancer
MeSH terms: Lymphoma
Study type: Interventional
Phase: Phase 1/Phase 2

Summary: 
      Background:

      - TRC102 is a new cancer treatment drug that may help improve the results of chemotherapy. It
      blocks tumor cells' attempts to repair damaged DNA, which may allow chemotherapy to kill the
      cells more easily. Researchers want to see how well it works with temozolomide, a
      chemotherapy drug that is designed to damage tumor cell DNA. These drugs will be given to
      people who have advanced solid tumors or lymphomas that have not responded to earlier
      treatments.

      Objectives:

      - To test the safety and effectiveness of TRC102 and temozolomide for advanced solid tumors
      and lymphomas.

      Eligibility:

      - Individuals at least 18 years of age who have advanced solid tumors or lymphomas that have
      not responded to earlier treatments.

      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.

        -  Participants will take TRC102 and temozolomide for 28-day cycles of treatment. They will
           take temozolomide and TRC 102 by mouth once a day on days 1-5. Participants will keep a
           diary to record doses and any side effects.

        -  Treatment will be monitored with frequent blood tests and imaging studies. Tumor samples
           will also be collected.

        -  Participants will continue their treatment as long as the cancer does not grow and there
           are no severe side effects.
    

Detailed description: 
      Background:

        -  Base excision repair (BER) of DNA repair pathway has been implicated in resistance to
           both alkylating and antimetabolite chemotherapy.

        -  TRC102 (methoxyamine HCl) acts through a novel mechanism to inhibit BER and has
           demonstrated the ability to potentiate the activity of the alkylating agent temozolomide
           (TMZ), in vitro and in vivo. We hypothesize that TRC102 can be safely co-administered

      with TMZ and would potentiate DNA damage caused by TMZ, resulting in antitumor responses.

      -Based on responses measured during the Phase I portion of the trial, we will further explore
      the efficacy of this combination in patients with metastatic colon carcinoma, nonsmall cell
      lung cancer (NSCLC), and granulosa cell ovarian cancer

      Primary Objective:

        -  To establish the safety, tolerability, and maximum tolerated dose (MTD) of oral TRC102
           in combination with oral TMZ in patients with refractory solid tumors

        -  Evaluate the pharmacokinetic (PK) profile of oral TRC102 when administered in
           combination with TMZ.

        -  To explore the response rate of this combination in patients with colon cancer, NSCLC,
           and granulosa cell ovarian cancer

      Secondary Objective:

      -To explore the progression free survival rate of this combination in patients with colon
      cancer, NSCLC, and granulosa cell ovarian cancer

      Exploratory Objectives:

        -  Investigate tumor genomic and transcriptomic alterations potentially associated with
           sensitivity and/or the development of resistance to TRC102 and temozolomide.

        -  Determine the effects of the study treatment on the level of histone gamma-H2AX in
           circulating tumor cells (CTCs) and tumor and correlate the gamma-H2AX response in tumor
           and CTCs

        -  Determine the effects of the study treatment on the levels of cleaved caspase 3,
           epithelial- mesenchymal transition, and APE in tumor and CTCs

        -  Determine and characterize the effects of study treatment on erythrocytes

        -  Characterize the clinical presentation of hemolysis observed in earlier study subjects
           and explore the possible mechanisms

      Eligibility:

        -  Phase I: histologically confirmed solid tumors that have progressed on standard therapy
           known to prolong survival or for which no standard treatment options exist

        -  Phase II: histologically confirmed adenocarcinoma of the colon post at least two lines
           of therapy, NSCLC post at least two lines of therapy, or granulosa cell ovarian cancer
           post at least one line of therapy

        -  No major surgery, radiation, or chemotherapy within 4 weeks prior to entering the study

        -  Adequate organ function

        -  Healthy adult volunteers greater than or equal to 18 years of age will be consented to
           donate research blood

      Please note: healthy adult volunteers will no longer be recruited to provide blood for this
      study as we will no longer perform the hemolysis analysis.

      Study Design: Phase I

        -  This is an open-label Phase I trial; traditional 3+3 design.

        -  Oral TRC102 and oral TMZ will be administered daily, days 1-5 in 28-day cycles

        -  Once the MTD is established, up to 15 additional patients will be enrolled at the MTD to
           further evaluate that dose for PK and PD endpoints for evidence of DNA damage and
           apoptosis.

        -  During the escalation phase, tumor biopsies will be optional. During the expansion
           phase, (once MTD is reached), mandatory paired tumor biopsies will be pursued in the 15
           additional patients enrolled to further evaluate PD endpoints.

      Phase II

        -  This is a 3-arm Simon 2-stage design trial evaluating independently the response rate of
           patients with colon, NSCLC, and granulosa cell ovarian cancer.

        -  Patients with a body surface area (BSA) of greater than or equal to 1.6 m(2) will
           receive 125 mg of TRC 102 and 150 mg/m2 of TMZ PO qday x 5 every 28 days (DL6). Patients
           with a BSA of <1.6 m(2) will receive 100 mg of TRC 102 and 150 mg/m2 of TMZ PO qday x 5
           every 28 days (DL5).. Each cycle will be 28 days.

        -  The accrual ceiling for the Phase II portion is 75 patients.

        -  Mandatory paired tumor biopsies will be pursued to further evaluate PD endpoints.
    

Intervention name(s): TRC102
Intervention type(s): Drug
Intervention description(s): TRC102 has been shown to potentiate the activity of temozolomide by preventing BER and allowing cleavage of TRC102 bound DNA, which will cause DNA strand breaks in cancer cells. We hypothesize that oral TRC102 can be safely co-administered with TMZ and would potentiate DNA damage caused by TMZ resulting in antitumor responses.
Intervention model: Single Group Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Solid Tumors; Lymphomas; DNA Damage; Pharmacodynamics; Pharmacokinetics