TRC102 and Temozolomide for Relapsed Solid Tumors and Lymphomas

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.

- Eligibility Criteria (Patients)

- 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 colorectal adenocarcinoma 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. Patients must have measurable disease.

- Age greater than18 years. Because no dosing or adverse event data are currently
available on the use of TRC102 in combination with TMZ in patients less than 18 years
of age, children are

excluded from this study.

- Patients enrolling in the expansion cohorts must have disease amenable to biopsy and
be willing to undergo pre-and post-treatment biopsies.

- ECOG performance status less than 2 (Phase I), less than or equal to 1(Phase II).

- Life expectancy of greater than 3 months

- Patients must have normal organ and marrow function as defined below:

- Absolute neutrophil count greater than 1,500/mcL

- Hemoglobin greater than or equal to 10 g/dL without transfusion within 1 week prior to
enrollment

Platelets greater than 100,000/mcL

Total bilirubin less than or equal to1.5 X institutional ULN

AST(SGOT)/ALT(SGPT) less than 3 X institutional upper limit of normal; 5.0 x ULN in cases
of liver metastases

creatinine less than or equal to 1.5 X institutional ULN

OR

creatinine clearance greater than 60 mL/min/1.73 m2 for patients with creatinine levels
greater than 1.5 mg/dL

-The effects of study drug 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; abstinence) prior to study entry and for the

duration of study participation and for at least 3 months after dosing with study drugs
ceases. Should a woman become pregnant or suspect she is pregnant while she or her partner
is participating in this study, she should inform her treating physician

immediately. Men treated or enrolled on this protocol must also agree to use adequate
contraception prior to the study, for the duration of study participation, and 3 months
after completion of study drug administration.

- Patients must have completed any chemotherapy, radiation therapy, or biologic therapy
greater than or equal to 4 weeks (or 5 half-lives, whichever is shorter) prior to
entering the study (6 weeks for nitrosoureas or mitomycin C). Patients must be greater
than or equal to 2 weeks since any prior administration of a study drug in a Phase 0
or equivalent study and greater than or equal to 1 week from palliative radiation
therapy. Patients must have recovered to eligibility levels from prior toxicity or
adverse events. Treatment with bisphosphonates is permitted.

- Patients must be able to swallow whole tablets or capsules; nasogastric or G-tube
administration is not allowed.

- Ability to understand and the willingness to sign a written informed consent document
and to undergo tumor biopsies in the expansion phase.

Exclusion Criteria (Patients)

- Patients who are actively receiving any other investigational agents.

- Patients with active brain metastases or carcinomatous meningitis are excluded from
this clinical trial. Patients with treated brain metastases, whose brain metastatic
disease has remained stable for greater than or equal to 4 weeks without requiring
steroid and anti-seizure medications are eligible to participate.

- Phase II only: No other prior malignancies are allowed except for the following:

- Adequately managed stage 0 (carcinoma in situ), I, or II basal cell or squamous
cell carcinoma from which the patient is currently in complete remission.

- Any other cancer from which the patient has been disease-free for three years.

- Adequately managed stage I or II well differentiated thyroid or prostate cancer
is also eligible, wherein the patient is not required to be in complete
remission.

- Phase II only: patients with colorectal cancer with known MSI-high disease who have
not previously been treated with immunotherapy or who have refused treatment with
immunotherapy.

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to TRC102 or TMZ.

- Uncontrolled intercurrent illness including, but not limited to, serious untreated
infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
arrhythmia, or psychiatric illness/social situations that would limit compliance with
study requirements.

- Pregnant women are excluded from this study because the effects of the study drugs on
the developing fetus are unknown. Because there is an unknown but potential risk for
adverse events in nursing infants secondary to treatment of the mother with the study
drugs, breastfeeding should be discontinued prior to the first dose of study drug and
women should refrain from nursing throughout the treatment period and for 3 months
following the last dose of study drug.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
possible PK interactions with TRC102.

(Healthy volunteer blood donors)

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.

- Age greater than 18 years; hemoglobin greater than or equal to 12 g/dL; no history of
bleeding problems; not taking aspirin or any medication that may affect erythrocyte
biochemistry

- Willingness to sign the healthy volunteer informed consent form.