This study will test the safety of an experimental drug, 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG), in patients with solid tumors or lymphomas. It will determine how much 17-DMAG can be given safely and examine how the body responds to the drug. 17-DMAG has shown some anti-cancer effects against tumors in laboratory tests and in animal studies. It has not previously been tested in humans.

Patients 18 years of age and older with a solid tumor cancer or lymphoma for which effective standard treatments are not available may be eligible for this study. Upon enrollment, participants are evaluated with a medical history and physical examination, blood and urine tests, electrocardiogram (EKG) and chest X-ray, diagnostic imaging studies (CT or MRI) to assess the extent of the cancer. In addition, patients undergo the following tests and procedures:

-17-DMAG treatment - 17-DMAG doses are infused through a vein twice a week for 4 weeks, unless too many side effects develop. Each infusion lasts about 1 hour. Treatment may continue beyond 4 weeks in patients whose tumor does not grow and who do not experience severe side effects. After 8 weeks of treatment, the patient's response to the drug is evaluated with a physical examination, scans, and X-rays.

-Blood studies - Blood work includes the following:

2 tablespoons of blood is drawn twice a week (before each drug dose) to assess how kidney, liver, bone marrow, and clotting mechanisms are functioning.

13 tablespoons of blood is drawn twice during the first 4 weeks of treatment to look for drug effects in the blood.

On the first day of 17-DMAG treatment, 1 to 2 teaspoons of blood is drawn before the drug infusion, after the infusion is finished, and another 10 times over the next 48 hours to examine how the body breaks down and eliminates the drug.

-24-hour urine collection - On the first day of 17-DMAG treatment, patients collect all their urine for 24 hours after the drug infusion to study how the body breaks down and eliminates the drug.

-Imaging studies - X-rays and scans are done to evaluate the size and extent of tumor.

-Tumor biopsy - If it can be done safely, a small piece of tumor is surgically removed before treatment starts and again during the first week of treatment and the fourth week of treatment to examine the effects of 17-DMAG on the tumor.

Condition	Treatment or Intervention	Phase
Neoplasms Lymphoma	Drug: 17-DMAG	Phase I

The primary objective is to define the maximum tolerable dose (MTD), dose-limiting toxicities (DLT) and toxicity profile of 17-DMAG administered as a 1 h infusion twice weekly for 4 weeks. Secondary objectives are to characterize the effects of 17-DMAG on client proteins, to estimate a dose of 17-DMAG at which some client protein effect is noted in a majority of patients, to evaluate peripheral blood mononuclear cells (PBMCs) as surrogates for tumor tissue in evaluating the effect of 17-DMAG on client proteins, to evaluate the expression of CAIR-1/BAG-3, a putative geldanamycin resistance protein and its relationship to client protein degradation, and to define the pharmacokinetics 17-DMAG given on this administration schedule. Population: Patients with solid tumors or lymphomas for which standard therapy is either unavailable or thought to provide only minimal patient benefit who meet eligibility criteria will be enrolled. Design: Rapid dose escalation in cohorts of single patients will occur. Dose level may be escalated in the next single patient if no grade greater than or equal to 2 drug related toxicity develops in the initial single patient over a 4-week course. If the second patient does not develop greater than or equal to grade 2 drug-related toxicity after a 4 week course, then dose level will be escalated again for the subsequent patient enrolled. One patient per dose level will be treated until one patient exhibits DLT or two patients exhibit grade greater than or equal to 2 drug related toxicity during the first course. At that point, the dose level that triggered the change will be expanded to 3 patients. If 0 of 3 patients develop DLT at this dose, escalation will continue in cohorts of 3 patients each. If a DLT is observed in the initial 3 patients in the first course at any dose level, the cohort will be expanded up to 6 patients. If a second DLT is observed, then dose escalation will stop, and up to 6 patients will be added to the next lower cohort. If no more than 1 of 6 patients in a dose level has DLT, then dose escalation will be permitted. The MTD or recommended phase 2 dose will be the dose level at which no more than 1 of 6 patients experience DLT and the dose below that at which at least 2 (of up to 6) patients have DLT as result of the drug. Ten additional patients will be treated at the recommended phase II dose in order to refine toxicity assessment and to obtain reasonable amounts of biologic data. Courses can be repeated, if toxicity has resolved and tumor has not progressed. Intrapatient dose escalation is allowed if a) there is no DMAG-related toxicity greater than grade 1 after 2 courses, b) higher doses have been evaluated without DLT in at least 1 patient and c) disease has not progressed.

Genders Eligible for Study:  Both

Criteria

INCLUSION CRITERIA
Patients must have histologically confirmed (at the treating institution) solid tumor malignancy or lymphoma that is metastatic or unresectable and for which standard curative or palliative measures do not exist or are associated with minimal patient survival benefit (as defined by the patient and/or their physician). Enrollment of patients with tumors that can be safely biopsied is encouraged. Measurable disease is not required.
Patients must have recovered to less than grade 1 CTCAEv3 from toxicity of prior chemotherapy or biologic therapy and must not have had prior chemotherapy or biologic therapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C, 8 weeks for UCN-01). Patients must be at least 1 month since any prior radiation or major surgery. Patients on bisphosphonates for any cancer or on hormone therapy for prostate cancer, however, will not need to discontinue this therapy in order to be eligible. However, prostate cancer patients will need to have metastatic prostate cancer that has progressed despite hormonal therapy. Castrate testosterone levels occur within hours after castration and within 2-3 weeks of a LHRH agonist. The current standard is to continue androgen suppression despite progressive disease.
Age greater than or equal to 18 years. Because no dosing or adverse event data are currently available on the use of 17-DMAG in patients less than 18 years of age, children are excluded from this study. Appropriate studies in the pediatric age group may be undertaken as indicated.
ECOG performance status less than or equal to 2 (Karnofsky greater than or equal to 60%).
Life expectancy of greater than 3 months.
3.1.6 Patients must have normal organ and marrow function as defined below:
Hb greater than 8 g/dL
leukocytes greater than or equal to 3,000/ microL
absolute neutrophil count greater than or equal to 1,500/ microL
platelets greater than or equal to 100,000/ microL
total bilirubin within normal institutional limits
AST (SGOT)/ALT (SGPT) less than or equal to 1 X institutional upper limit of normal
creatinine within normal institutional limits
OR
creatinine clearance greater than or equal to 60 mL/min/1.73 m2 for patients with creatinine levels above institutional normal.
PT, PTT within normal limits
The effects of 17-DMAG on the developing human fetus are unknown. For this reason and because chemotherapeutic agents in general 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 or abstinence) prior to study entry and for the duration of study participation. Women of child bearing potential must have a negative pregnancy test in order to be eligible. 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.
EXCLUSION CRITERIA
Patients who have had chemotherapy, biologic therapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C, 8 weeks for UCN-01) prior to entering the study or those who have not recovered to less than or equal to grade 1 from adverse events due to agents administered more than 4 weeks earlier.
Patients may not be receiving any other investigational agents.
Patients with known brain metastases should be excluded from this clinical trial because of their poor prognosis and because they often develop progressive neurologic dysfunction that would confound the evaluation of neurologic and other adverse events. However, patients who have had treatment for their brain metastases and whose brain metastatic disease status has remained stable for at least 6 months without steroids or anti-seizure medications may be enrolled at the discretion of the principal investigator.
History of allergic reactions attributed to compounds of similar chemical or biologic composition to 17-DMAG (geldanamycin, 17-AAG).
Uncontrolled intercurrent illness including, but not limited to ongoing or active uncontrolled infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. Patients taking more than preventive doses of aspirin or NSAIDs, or on full anti-coagulation on a regular basis will also be excluded due to hemorrhage noted in animal studies.
Pregnant women are excluded from this study because 17-DMAG is an 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 17-DMAG, breastfeeding should be discontinued if the mother is treated with 17-DMAG.
Patients with immune deficiency are at increased risk of lethal infections when treated with marrow-suppressive therapy. Therefore, patients with known immune deficiency syndromes or who are HIV positive will be excluded from the study. HIV-positive patients with disease controlled by combination anti-retroviral therapy are excluded from the study because of possible pharmacokinetic interactions with 17-DMAG. Appropriate studies will be undertaken in these patients when indicated.
Patients with baseline hyponatremia less than 130 mmol/L or orthostatic hypotension greater than Grade 2 (requiring more than brief fluid replacement or other therapy or with physiologic consequences) and/or not corrected to serum sodium greater than 130 mmol/L or orthostatic hypotension at most Grade 1 (changes, intervention not needed) with up to 2 L 0.9% sodium chloride infusion.
INCLUSION OF WOMEN AND MINORITIES
Both men and women and members of all races and ethnic groups are eligible for this trial.

Maryland
      National Cancer Institute (NCI), 9000 Rockville Pike,  Bethesda,  Maryland,  20892,  United States; Recruiting

Study ID Numbers:  040218; 04-C-0218
Record last reviewed:  June 14, 2004
Last Updated:  June 14, 2004
Record first received:  June 18, 2004
ClinicalTrials.gov Identifier:  NCT00086008
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2004-10-22