A Phase 1, Dose Escalation Study of the Safety, Tolerability, and Pharmacokinetics of Intravenous Dimethane Sulfonate (DMS612) in Advanced Malignancies

Background:

- The dimethane sulfonates are a group of agents that were identified as active against
renal cell carcinoma in the NCI anticancer drug screen.

- In vitro studies showed that dimethane sulfonates have properties in common with
alkylating agents, but are unlike conventional alkylators (such as nitrogen mustards,
BCNU, or busulfan) in that they are active against renal cell carcinoma (RCC).

Objective:

Primary:

-To determine dose-limiting toxicity (DLT), MTD and recommended phase II dose (RPTD) of
dimethane sulfonate (DMS612, NSC 281612) when administered by intravenous (IV) bolus on day 1
and 2 of a 21-day cycle.

Eligibility:

- Patients must have histologically confirmed solid tumor malignancy or lymphoma that is
metastatic or unresectable and for which standard curative or palliative measures do not
exist or are no longer effective.

- Any prior chemotherapy therapy is allowed in this protocol. No more than 2 prior
cytotoxic chemotherapy regimens are allowed.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of Dimethane sulfonate in patients less than 18 years of
age, children are excluded from this study but will be eligible for future pediatric
phase 1 single-agent trials.

- ECOG performance status 0-2 (Karnofsky greater than or equal to 60%,).

- Life expectancy of 3 months or greater.

- Patients must have acceptable organ and marrow function as defined below: leukocytes
greater than or equal to 3,000/mcL, absolute neutrophil count greater than or equal to
1,500/mm(3), platelets greater than or equal to 100,000/, mm(3) total bilirubin within
normal institutional limits, AST(SGOT)/ALT(SGPT), less than or equal to 2.5 times the
institutional upper limit of normal, creatinine within normal institutional limits or
creatinine clearance greater than 50mL/min for patients with creatinine levels above
institutional normal.

Design:

This is a Phase I study of the safety, pharmacokinetics, pharmacodynamics and antitumor
activity of IV DMS612, NSC 281612, designed as an open-label, dose-escalation study to
determine the RPTD of DMS612, NSC 281612 based on safety and pharmacokinetics. With the
02/09/2015 amendment and change in schedule to evaluate a day 1 and 2 dosing every 6 weeks
the following schema will be used:

Dose Level Dose of NSC 281612 Escalation (%)

- 1 3.5 mg/m2 on Day 1 and 2 -33

4A 4.5 mg/m2 on Day 1 and 2 ---

5A 6 mg/m2 on Day 1 and 2 33

6A 8 mg/m2 on Day 1 and 2 67

7A 10.5 mg/m2 on Day 1 and 2 33

7B 10.5 mg/m2 on Day 1 and 2 q 6 weeks ---

8A 14 mg/m2 on Day 1 and 2 33

8B 14 mg/m2 on Day 1 and 2 q 6 weeks --

- INCLUSION CRITERIA:

- Patients must have histologically confirmed solid tumor malignancy or lymphoma that is
metastatic or unresectable and for which effective therapy does not exist or is no
longer effective.

- Any prior chemotherapy therapy is allowed in this protocol. No more than 2 prior
cytotoxic chemotherapy regimens are allowed for eligibility. Non-myelotoxic therapies
such as sunitinib and sorafenib or everolimus are not considered "cytotoxic
chemotherapies".Patients must be greater than or equal to 4 weeks from prior radiation
or cytotoxic chemotherapy, except greater than or equal to 6 weeks for mitomycin C and
nitrosoureas; greater than or equal to 2 weeks from hormonal therapy; greater than or
equal to 4 weeks from prior experimental therapy; greater than or equal to 4 weeks
from monoclonal antibody therapy (cetuximab, bevacizumab), greater than or equal to 2
weeks from sorafenib, sunitinib or temsirolimus and greater than or equal to 8 weeks
from prior UCN01 treatment. Patients with prostate cancer may continue ongoing LHRH
agonist therapy. Patients with bone metastases or hypercalcemia who began intravenous
bisphosphonate treatment prior to study entry may continue this treatment.

- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of dimethane sulfonate in patients less than 18 years
of age, children are excluded from this study but will be eligible for future
pediatric phase 1 single-agent trials.

- ECOG performance status 0-2 (Karnofsky greater than or equal to 60%,).

- Life expectancy of 3 months or greater.

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

- leukocytes greater than or equal to 3,000/mm(3)

- absolute neutrophil count greater than or equal to 1,500/ mm(3)

- platelets greater than or equal to 100,000/ mm(3)

- total bilirubin within normal institutional limits

- AST(SGOT)/ALT(SGPT) less than or equal to 2.5 times institutional upper limit of
normal

- creatinine within normal institutional limits OR

- 24 hour urine creatinine clearance greater than 50 mL/min/1.73 m(2) for patients
with creatinine levels above institutional normal (may use creatinine clearance
Cockcroft-Gault Equation).

- The effects of dimethane sulfonate on the developing human fetus are unknown. For this
reason and because alkylating agents 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 and for at least 3
months after study participation. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately.

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

- Willing to comply with study procedures and follow-up.

EXCLUSION CRITERIA:

- Patients who have not recovered (CTC less than or equal to grade I) from adverse
events due to prior treatments

- Patients may not have received more than 2 prior cytotoxic regimens.

- Patients may not be receiving any other investigational agent with therapeutic
anticancer intent.

- Patients with history of CNS metastasis, unless control has been achieved with either
radiation or surgical resection at least 3 months prior to enrollment on study.

- Patients who have had radiation to the pelvis or other bone marrow-bearing sites will
be considered on a case by case basis and may be excluded if the bone marrow reserve
is not considered adequate (greater than 25% of bone marrow irradiated).

- Uncontrolled medical illness including, but not limited to, ongoing or active
infection, chronic or acute hepatitis, renal failure, symptomatic congestive heart
failure, myocardial infarction within the last 6 months, 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 DMS612 is likely to have
toxicities similar to the alklyating agents 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 DMS612,
breastfeeding should be discontinued if the mother is treated with DMS612.

- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for pharmacokinetic interactions with DMS612. 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 are not eligible for the study if taking cytochrome P450-inducing
anticonvulsants. This applies to patients with brain metastasis or those taking
anticonvulsant for another reason (ie. Epilepsy).

- Patients diagnosed with alcoholism may not be treated with disulfiram.

- Patients may not be receiving agents thought to inhibit or induce the cytochrome p450
isoenzyme CYP3A4.