Combination Chemotherapy in Treating Patients With Metastatic or Unresectable Solid Tumors

A Phase I Study of 17-N-Allylamino-17-Demethoxy Geldanamycin (17-AAG, NSC# 330507) in Combination With Docetaxel in Patients With Advanced Solid Tumors

This phase I trial is studying the side effects and best dose of combination chemotherapy in treating patients with metastatic or unresectable solid tumors. Drugs used in chemotherapy, such as docetaxel and 17-N-allylamino-17-demethoxygeldanamycin, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining more than one drug may kill more tumor cells.

Study Overview

• Status: Completed
• Conditions: Recurrent Prostate Cancer; Unspecified Adult Solid Tumor, Protocol Specific; Stage IV Prostate Cancer
• Intervention / Treatment: Drug: tanespimycin; Drug: docetaxel

Detailed Description

OBJECTIVES:

I. Determine the maximum tolerated dose of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) administered with docetaxel in patients with progressive metastatic prostate cancer or other progressive metastatic or unresectable solid tumors.

II. Determine the pharmacokinetics of this regimen in these patients.

OUTLINE: This is a dose-escalation study of 17-N-allylamino-17-demethoxygeldanamycin (17-AAG). Patients are assigned to 1 of 2 treatment groups.

Group 1: Patients receive docetaxel IV over 1 hour and 17-AAG IV over 1-2 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

Group 2: Patients receive docetaxel IV over 30 minutes and 17-AAG as in group 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients per group receive escalating doses of 17-AAG until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity. Up to 20 additional patients (10 per group) are treated at the MTD.

Patients are followed every 2-3 months.

• Study Type: Interventional
• Enrollment (Actual): 80
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • New York, New York, United States, 10065
      • Memorial Sloan-Kettering Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Histologically confirmed metastatic or unresectable malignancy for which standard curative or palliative therapy does not exist or is no longer effective

• Progressive disease manifested by the following parameters

  • For prostate cancer:

    • Must have castrate, metastatic disease defined by disease progression after surgical castration or treatment with a gonadotropin-releasing hormone (GnRH) analog (testosterone level less than 50 ng/mL)

      • Patients who have not undergone surgical orchiectomy should continue on medical therapies to maintain castrate levels of testosterone
    • Progressive metastatic disease on imaging studies (bone scan, CT scan, or MRI) OR metastatic disease and a rising prostate-specific antigen (PSA)
    • Biochemical progression indicated by at least 3 rising PSA values (obtained at least 1 week apart) from a baseline OR 2 rising PSA values (more than 1 month apart), where the percentage increase over the range of values is at least 25%
    • Patients who have received an antiandrogen as part of first-line hormonal therapy must have shown progression of disease off of the antiandrogen prior to study enrollment

  • For other solid tumors:

    • Development of new lesions or an increase in pre-existing lesions by bone scintigraphy, CT scan, MRI, positron emission tomography, or physical examination
    • Patients whose sole criterion for progression is an increase in a biochemical marker (e.g., carcinoembryonic antigen or CA 15-3) or an increase in symptoms are not eligible
• Patients with metastatic disease must not be progressing to the extent as to require palliative treatment within 4 weeks of study entry
• No active brain metastases
• Performance status - Karnofsky 70-100%
• More than 6 months
• WBC at least 3,000/mm^3
• Absolute neutrophil count at least 1,500/mm^3
• Platelet count at least 100,000/mm^3
• Bilirubin ≤ 1.5 times upper limit of normal (ULN)
• AST and ALT < 1.5 times ULN
• PT ≤ 1.1 times ULN
• Creatinine no greater than 1.4 mg/dL or within ULN
• Creatinine clearance greater than 55 mL/min
• No prior history of pulmonary toxicity after receiving anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine)
• No dyspnea ≥ grade 2 at rest on room air
• No requirement for supplementary oxygen therapy or oxygen saturations ≤ 88%
• No clinically significant pulmonary comorbidities that require medication (e.g., severe chronic obstructive pulmonary disease that could predispose patient to pulmonary toxicity)
• QTc ≤ 450 msec for male patients (470 for female patients)
• LVEF > 40% by echocardiogram or MUGA

• Echocardiogram or MUGA required for patients with any of the following:

  • Myocardial infarction > 1 year ago
  • NYHA class I or II CHF
  • Atrial fibrillation
  • Right or left bundle branch block by EKG
• No history of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)
• No myocardial infarction within the past year
• No active ischemic heart disease within the past year
• No New York Heart Association (NYHA) class III or IV congestive heart failure (CHF)
• No poorly controlled angina
• No uncontrolled dysrhythmia
• No congenital long QT syndrome
• No left bundle branch block
• No other significant cardiac disease
• No prior history of cardiac toxicity after receiving anthracyclines such as doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone hydrochloride, bleomycin, or carmustine
• Not pregnant or nursing
• Negative pregnancy test
• Fertile patients must use effective contraception
• No history of severe hypersensitivity reaction to paclitaxel, docetaxel, or polysorbate 80
• No ongoing or active infection
• No psychiatric illness or social situation that would preclude study compliance
• No grade 2 or greater symptomatic peripheral neuropathy
• No allergy to eggs or egg products
• No other concurrent uncontrolled illness
• At least 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin)
• See Disease Characteristics
• At least 4 weeks since prior radiotherapy and recovered
• No concurrent radiotherapy to sole measurable lesion
• No prior mantle-field radiotherapy
• See Disease Characteristics
• No concurrent surgery for sole measurable lesion
• Recovered from prior therapy
• At least 1 week since prior ketoconazole and recovered
• At least 4 weeks since prior investigational anticancer therapeutic drugs
• No concurrent combination antiretroviral therapy for HIV-positive patients
• No concurrent medications that prolong QTc interval

• No concurrent medication used to control arrhythmias

  • Calcium blockers and beta blockers allowed
• No other concurrent investigational agents
• No other concurrent anticancer agents or therapies (investigational or commercial)

• No concurrent CYP3A4 inhibitors, including any of the following:

  • Fluconazole
  • Itraconazole
  • Ketoconazole
  • Macrolide antibiotics (azithromycin, clarithromycin, erythromycin, or troleandomycin)
  • Nifedipine
  • Verapamil
  • Diltiazem
  • Cyclosporine
  • Grapefruit juice

• No concurrent CYP3A4 inducers, including any of the following:

  • Carbamazepine
  • Phenobarbital
  • Phenytoin
  • Rifampin

• No concurrent herbal extracts or tinctures with CYP3A4 inhibitory activity, including any of the following:

  • Hydrastis canadensis (goldenseal)
  • Hypericum perforatum (St. John's wort)
  • Uncaria tomentosa (cat's claw)
  • Echinacea angustifolia roots
  • Trifolium pratense (wild cherry)
  • Matricaria chamomilla (chamomile)
  • Glycyrrhiza glabra (licorice)
  • Dillapiol
  • Hypericin
  • Naringenin
• Concurrent CYP3A4 substrates allowed

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group I; Patients receive docetaxel IV over 1 hour and 17-AAG IV over 1-2 hours on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Drug: tanespimycin; Given IV; Other Names: 17-AAG; Drug: docetaxel; Given IV; Other Names: Taxotere; RP 56976; TXT
Experimental: Group II; Patients receive docetaxel IV over 30 minutes and 17-AAG as in group 1. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.	Drug: tanespimycin; Given IV; Other Names: 17-AAG; Drug: docetaxel; Given IV; Other Names: Taxotere; RP 56976; TXT

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Time Frame
Maximum tolerated dose determined by dose-limiting toxicities assessed using the NCI Common Toxicity Criteria (CTC) version 2.0	28 days

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)

Study record dates

Study Major Dates

• Study Start: February 1, 2003
• Primary Completion (Actual): January 1, 2008
• Study Completion (Actual): March 1, 2010

Study Registration Dates

• First Submitted: April 7, 2003
• First Submitted That Met QC Criteria: April 8, 2003
• First Posted (Estimate): April 9, 2003

Study Record Updates

• Last Update Posted (Estimate): June 17, 2014
• Last Update Submitted That Met QC Criteria: June 16, 2014
• Last Verified: December 1, 2012

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Diseases; Prostatic Neoplasms; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Tubulin Modulators; Antimitotic Agents; Mitosis Modulators; Docetaxel
• Other Study ID Numbers: NCI-2012-01436 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); U01CA069856 (U.S. NIH Grant/Contract); P30CA008748 (U.S. NIH Grant/Contract); 03-006 (Other Identifier: Memorial Sloan-Kettering Cancer Center); NCI-5878; CDR0000287199; MSKCC-03006; 5878 (Other Identifier: CTEP)