Alvespimycin Hydrochloride in Treating Patients With Metastatic or Unresectable Solid Tumors

National Cancer Institute (NCI)

Status and phase: Completed; Phase 1

Conditions: Recurrent Squamous Cell Carcinoma of the Hypopharynx; Stage IV Gastric Cancer; Stage IV Lymphoepithelioma of the Oropharynx; Stage IV Renal Cell Cancer; Recurrent Melanoma; Stage IV Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage III Adenoid Cystic Carcinoma of the Oral Cavity; Stage IV Squamous Cell Carcinoma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Mucoepidermoid Carcinoma of the Oral Cavity; Recurrent Verrucous Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Oropharynx; Stage IV Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage III Renal Cell Cancer; Stage IV Squamous Cell Carcinoma of the Hypopharynx; Stage IV Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Recurrent Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Ovarian Epithelial Cancer; Stage III Verrucous Carcinoma of the Oral Cavity; Stage III Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Untreated Metastatic Squamous Neck Cancer With Occult Primary; Stage III Mucoepidermoid Carcinoma of the Oral Cavity; Stage III Squamous Cell Carcinoma of the Oropharynx; Stage IV Mucoepidermoid Carcinoma of the Oral Cavity; Stage IV Colon Cancer; Recurrent Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage III Midline Lethal Granuloma of the Paranasal Sinus and Nasal Cavity; Stage III Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Nasopharynx; Recurrent Breast Cancer; Stage III Squamous Cell Carcinoma of the Hypopharynx; Stage III Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Recurrent Salivary Gland Cancer; Stage III Gastric Cancer; Recurrent Squamous Cell Carcinoma of the Paranasal Sinus and Nasal Cavity; Stage IV Salivary Gland Cancer; Recurrent Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Stage III Basal Cell Carcinoma of the Lip; Stage IV Ovarian Epithelial Cancer; Stage IV Squamous Cell Carcinoma of the Lip and Oral Cavity; Recurrent Adenoid Cystic Carcinoma of the Oral Cavity; Stage III Inverted Papilloma of the Paranasal Sinus and Nasal Cavity; Male Breast Cancer; Recurrent Basal Cell Carcinoma of the Lip; Stage IIIB Breast Cancer; Stage III Ovarian Epithelial Cancer; Stage III Melanoma; Recurrent Renal Cell Cancer; Stage IV Adenoid Cystic Carcinoma of the Oral Cavity; Recurrent Gastric Cancer; Stage IV Basal Cell Carcinoma of the Lip; Stage IIIC Breast Cancer; Recurrent Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Squamous Cell Carcinoma of the Larynx; Stage III Colon Cancer; Recurrent Verrucous Carcinoma of the Oral Cavity; Stage IV Esthesioneuroblastoma of the Paranasal Sinus and Nasal Cavity; Stage IV Lymphoepithelioma of the Nasopharynx; Recurrent Lymphoepithelioma of the Oropharynx; Stage IV Verrucous Carcinoma of the Larynx; Unspecified Adult Solid Tumor, Protocol Specific; Stage IV Verrucous Carcinoma of the Oral Cavity; Recurrent Colon Cancer; Stage III Verrucous Carcinoma of the Larynx; Stage III Squamous Cell Carcinoma of the Nasopharynx; Recurrent Squamous Cell Carcinoma of the Larynx; Stage III Lymphoepithelioma of the Oropharynx; Stage III Squamous Cell Carcinoma of the Larynx; Recurrent Squamous Cell Carcinoma of the Nasopharynx; Recurrent Metastatic Squamous Neck Cancer With Occult Primary; Stage IV Squamous Cell Carcinoma of the Nasopharynx; Stage IV Prostate Cancer; Stage III Salivary Gland Cancer; Recurrent Prostate Cancer; Stage IV Melanoma; Stage IV Breast Cancer

Treatments: Other: laboratory biomarker analysis; Other: pharmacological study; Drug: alvespimycin hydrochloride

Study type: Interventional

Funder types: NIH

Identifiers

NCT00089362

04-053

NCI-2012-01455

NCI-6542

U01CA069856 (U.S. NIH Grant/Contract)

CDR0000378288

MSKCC-04053

Details and patient eligibility

About

This phase I trial is studying the side effects and best dose of alvespimycin hydrochloride in treating patients with metastatic or unresectable solid tumors. Drugs used in chemotherapy, such as alvespimycin hydrochloride, work in different ways to stop tumor cells from dividing so they stop growing or die.

Full description

PRIMARY OBJECTIVES:

I. Determine the toxic effects and maximum tolerated dose of 17-dimethylaminoethylamino-17-demethoxygeldanamycin (17-DMAG) in patients with metastatic or unresectable solid tumors.

SECONDARY OBJECTIVES:

II. Determine the effects of this drug on the expression of Hsp90 client proteins in normal and tumor tissue samples from these patients.

OUTLINE: This is a dose-escalation study.

Patients receive alvespimycin hydrochloride IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Cohorts of 1-2 patients receive accelerated escalating doses of alvespimycin hydrochloride until at least 1 of 2 patients experience dose-limiting toxicity (DLT). Cohorts are then expanded to 3-6 patients who receive escalating doses (in a standard manner) of alvespimycin hydrochloride 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 DLT. Once the MTD is determined, 10 additional patients are treated at that dose.

Enrollment: 30 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria:

• Histologically confirmed solid tumor, including, but not limited to, the following:

  • Prostate
  • Breast
  • Ovary
  • Colon
  • Kidney
  • Head and neck
  • Stomach
  • Melanoma

• Metastatic or unresectable disease

• No standard curative or palliative therapy exists or is no longer effective

• Progressive disease as indicated by the following:

  • Non-prostate cancer

    • New lesions or increase in pre-existing lesions on bone scintigraphy, CT scan, MRI, or by physical examination
    • No increase in biochemical markers (e.g., carcinoembryonic antigen or CA-15-3) or symptoms as sole evidence of disease progression

  • Prostate cancer

    • Must have castrate metastatic disease (i.e., disease progression after castration or treatment with a gonadotropin-releasing hormone [GnRH] analog)

      • Patients who have not undergone surgical orchiectomy must continue with medical therapy (i.e., GnRH analogs) to maintain castrate levels of serum testosterone < 50 ng/dL
      • Patients who received an antiandrogen as part of first-line hormonal therapy must show disease progression after discontinuing treatment

    • Progressive metastatic disease on imaging studies (e.g., bone scan, CT scan, or MRI) OR metastatic disease and a rising prostate-specific antigen (PSA) allowed

      • Biochemical progression is defined as a minimum of 3 rising PSA values from baseline obtained at least 1 week apart OR 2 rising PSA values obtained more than 1 month apart, with >= 25% increase in value

• No active brain metastases

• Hormone receptor status:

  • Not specified

• Male or female

• Performance status - Karnofsky 70-100%

• Performance status - ECOG 0-1

• More than 6 months

• WBC >= 3, 000/mm^3

• Absolute neutrophil count >= 1, 500/mm^3

• Platelet count >= 100,000/mm^3

• Bilirubin =< 1.5 times upper limit of normal (ULN)

• AST and ALT < 1.5 times ULN

• PT normal

• Creatinine =< 1.4 mg/dL

• Creatinine clearance > 55 mL/min

• QTc < 450 msec for male patients (470 msec for female patients)

• LVEF > 40% by MUGA

• 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 class III or IV congestive heart failure

• No congenital long QT syndrome

• No left bundle branch block

• No poorly controlled angina

• No history of uncontrolled dysrhythmias or requiring antiarrhythmic drugs

  • Calcium blockers and beta blockers allowed

• No other significant cardiac disease

• Oxygen saturation > 88%

• Dyspnea < grade 2 at rest on room air

• No clinically significant pulmonary comorbidity (e.g., severe chronic obstructive pulmonary disease)

• No requirement for supplemental oxygen

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception

• No active or ongoing infection

• No symptomatic peripheral neuropathy >= grade 2

• No psychiatric illness or social situation that would preclude study compliance

• No other uncontrolled illness

• More than 4 weeks since prior chemotherapy (6 weeks for mitomycin and nitrosoureas)

• At least 1 week since prior ketoconazole

• More than 4 weeks since prior radiotherapy

• Recovered from all prior therapy

• More than 4 weeks since prior investigational anticancer therapeutic drugs

• No concurrent combination antiretroviral therapy for HIV-positive patients

• No concurrent administration of any of the following herbal remedies:

  • 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

• No other concurrent investigational agents

• No other concurrent anticancer agents or therapies

Trial design

Primary purpose: Treatment

Allocation: N/A

Interventional model: Single Group Assignment

Masking: None (Open label)

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30 participants in 1 patient group

Treatment (alvespimycin hydrochloride)

Experimental group

Description:

Patients receive alvespimycin hydrochloride IV over 1 hour on days 1, 8, and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity. Cohorts of 1-2 patients receive accelerated escalating doses of alvespimycin hydrochloride until at least 1 of 2 patients experience DLT. Cohorts are then expanded to 3-6 patients who receive escalating doses (in a standard manner) of alvespimycin hydrochloride until MTD is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience DLT. Once the MTD is determined, 10 additional patients are treated at that dose.

Treatment:

Drug: alvespimycin hydrochloride

Other: pharmacological study

Other: laboratory biomarker analysis