Methoxyamine, Cisplatin, and Pemetrexed Disodium in Treating Patients With Advanced Solid Tumors or Mesothelioma That Cannot Be Removed by Surgery or Mesothelioma That Is Refractory to Pemetrexed Disodium and Cisplatin or Carboplatin

PRIMARY OBJECTIVES:

I. To determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D) for
the combination of methoxyamine (TRC102) with pemetrexed (pemetrexed disodium) and cisplatin
in patients with advanced solid tumors. (Arm A) II. To describe the toxicities of TRC102
combined with pemetrexed and cisplatin at each dose studied. (Arm A) III. To describe
responses to the drug combination at each dose level. (Arm A) IV. To detect activity of the
combination of TRC102 and pemetrexed, as evidenced by tumor response in patients with
advanced malignant mesothelioma previously treated with pemetrexed and cisplatin. (Arm B)

SECONDARY OBJECTIVES:

I. To describe pharmacokinetic parameters of TRC102 given concurrent with pemetrexed and
cisplatin.

II. To evaluate the pharmacodynamic parameters of TRC102 given concurrently with pemetrexed
and cisplatin.

III. To explore the feasibility of establishing pleural and peritoneal effluent-derived cell
lines and to evaluate the response of cultured pleural and peritoneal mesothelioma cells to
cisplatin, pemetrexed, and TRC102.

IV. To document all objective clinical responses to TRC102 in combination with pemetrexed and
cisplatin.

OUTLINE: This is a phase I, dose-escalation study of methoxyamine, followed by a phase II
study. Patients are assigned to 1 of 2 treatment arms.

ARM A: Patients receive methoxyamine orally (PO) once daily (QD) on days 1-4, pemetrexed
disodium intravenously (IV) over 10 minutes, and cisplatin IV over 30-60 minutes on day 1.
Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or
unacceptable toxicity. Patients may continue methoxyamine and pemetrexed disodium beyond
cycle 6 if the patient continues to benefit from treatment at the discretion of the treating
physician.

ARM B: Patients receive methoxyamine PO QD on days 1-4 and pemetrexed disodium IV over 10
minutes on day 1. Treatment repeats every 21 days for up to 6 cycles in the absence of
disease progression or unacceptable toxicity. Patients may continue methoxyamine and
pemetrexed disodium beyond cycle 6 if the patient continues to benefit from treatment at the
discretion of the treating physician.

After completion of study treatment, patients are followed up for 8 weeks.

Inclusion Criteria:

- Arm A dose escalation: patients with histologically or cytologically proven advanced
solid tumors for which standard treatments are not available, or for whom the current
dose level of cisplatin in combination with pemetrexed is appropriate; =< 2 prior
cytotoxic chemotherapy regimen

- Arm A dose level 4 (75 mg/m^2 cisplatin): patients with histologically proven
chemotherapy-naive advanced unresectable solid tumors for which pemetrexed combined
with cisplatin is an indicated regimen

- Arm B (first stage of phase II of TRC102 and pemetrexed): patients with malignant
pleural or peritoneal mesothelioma who had progressed while being treated with or had
recurred within 6 months of being treated with pemetrexed and cisplatin or carboplatin
frontline; intervening treatment is allowed

- Prior pemetrexed is allowed except Arm A dose level 4 (cisplatin 75 mg/m^2)

- Eastern Cooperative Oncology Group (ECOG) performance status 0 -1 (Karnofsky >= 70%)

- Life expectancy of greater than 3 months

- Absolute neutrophil count >= 1,500/uL

- Platelets >= 100,000/uL

- Hemoglobin >= 10.0 g/dl

- Prothrombin time or international normalized ratio (INR) =< 1.5 x upper limit of
normal (ULN)

- Total bilirubin < 1.5 x ULN

- Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
[SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
=< 2.5 x institutional ULN or =< 5 x ULN if metastatic disease involves liver

- Serum creatinine =< 1.5 x ULN or a calculated creatinine clearance >= 60 ml/min/1.73
m^2 (Cockcroft-Gault method) for patients receiving combination of cisplatin and
pemetrexed and >= 45 ml/min/1.73 m^2 for patients receiving pemetrexed; 24 hour urine
for creatinine clearance is acceptable if the calculated creatinine clearance is
insufficient

- For patients enrolled in arm B (first stage of phase II of TRC102 and pemetrexed)
measurable disease is required according to the Response Evaluation Criteria in Solid
Tumors (RECIST) criteria for patients with solid tumors and modified RECIST criteria
as described by Byrne and Novak for patients with malignant pleural mesothelioma;
pleural effusion and ascites are not considered measurable disease

- Patients must be able to swallow whole capsules; nasogastric or gastrointestinal
(G)-tube administration is not allowed

- The effects of TRC102 on the developing human fetus are unknown; for this reason and
because TRC102 as well as other therapeutic agents used in this trial are known to be
teratogenic, 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, for the duration of study participation, and 4 months after completion of the
study drugs; 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 4
months after completion of TRC102, pemetrexed and cisplatin administration;
non-childbearing potential is defined as (by other then medical reasons): >= 45 years
of age and has not had menses for >= 2 years, amenorrheic for < 2 years without
hysterectomy and oophorectomy and a follicle-stimulating hormone value in the
postmenopausal range upon pretrial (screening) evaluation, or post hysterectomy,
oophorectomy or tubal ligation; documented hysterectomy or oophorectomy must be
confirmed with medical records of the actual procedure or confirmed by ultrasound;
tubal ligation must be confirmed with medical records of the actual procedure
otherwise the patient must be willing to use 2 adequate barrier methods throughout the
study, starting with the screening visit though 4 months after the last dose of study
drugs

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for
nitrosoureas or mitomycin C) prior to entering the study or those who have not
recovered from adverse events due to agents administered more than 4 weeks earlier;
patients who have had targeted therapy will be required to wait 2 weeks due to short
half-life of the drugs; treatment with bisphosphonates is permitted

- Patients who are 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

- History of allergic reactions attributed to compounds of similar chemical or biologic
composition to TRC102 or pemetrexed and cisplatin

- No studies have been performed to assess potential metabolic and transport
interactions of TRC102; as part of the enrollment/informed consent procedures, the
patient will be counseled on the risk of interactions with other agents, and what to
do if new medications need to be prescribed or if the patient is considering a new
over-the-counter medicine or herbal product; the case report form must capture the
concurrent use of all other drugs, over-the-counter medications, or alternative
therapies

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active
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 TRC102 is agent with the potential
for teratogenic or abortifacient effects; because there is an unknown but potential
risk for adverse events in nursing infants secondary to treatment of the mother with
TRC102, breastfeeding should be discontinued if the mother is treated with TRC102;
these potential risks may also apply to other agents used in this study

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
therapy are ineligible because of the potential for pharmacokinetic interactions with
TRC102; in addition, these patients are at increased risk of lethal infections when
treated with marrow-suppressive therapy; appropriate studies will be undertaken in
patients receiving combination antiretroviral therapy when indicated

- Patients with known disorders associated with hemolysis

- Patients with thromboembolic disease and on anticoagulation

- Patients with a prior cumulative cisplatin dose > 300 mg/m^2 (pertains to Arm A only)