AT13387 in Adults With Refractory Solid Tumors
| Status: | Completed |
|---|---|
| Conditions: | Breast Cancer, Cancer, Cancer |
| Therapuetic Areas: | Oncology |
| Healthy: | No |
| Age Range: | 18 - 120 |
| Updated: | 2/16/2018 |
| Start Date: | November 19, 2010 |
| End Date: | October 27, 2017 |
Phase I Study of the HSP-90 Inhibitor, AT13387, in Adults With Refractory Solid Tumors
Background:
- The experimental drug AT13387 has been shown to have some anticancer effects against tumor
cells by blocking a protein that affects other proteins inside certain cancer cells, and
helps to prevent the cancer cells from reproducing and spreading. AT13387 has not been tested
in humans, and researchers are interested in investigating whether it can be used to treat
solid tumors that have not responded to standard treatments.
Objectives:
- To investigate the safety and effectiveness of AT13387 in individuals with solid tumors.
Eligibility:
- Individuals at least 18 years of age who have solid tumors that have not responded to
standard treatments.
Design:
- Participants will be screened with a physical examination and medical history, as well
as blood tests and tumor imaging studies.
- AT13387 will be given in 28-day cycles of treatment. Participants will receive AT13387
twice a week (2 days in a row) for the first 3 weeks of the cycle, followed by a fourth
week without the drug.
- Participants will have regular blood and urine samples, imaging studies, eye
examinations, and tumor biopsies to monitor the effects of the treatment.
- Participants will continue treatment with AT13387 unless serious side effects develop or
the tumor stops responding to treatment.
- The experimental drug AT13387 has been shown to have some anticancer effects against tumor
cells by blocking a protein that affects other proteins inside certain cancer cells, and
helps to prevent the cancer cells from reproducing and spreading. AT13387 has not been tested
in humans, and researchers are interested in investigating whether it can be used to treat
solid tumors that have not responded to standard treatments.
Objectives:
- To investigate the safety and effectiveness of AT13387 in individuals with solid tumors.
Eligibility:
- Individuals at least 18 years of age who have solid tumors that have not responded to
standard treatments.
Design:
- Participants will be screened with a physical examination and medical history, as well
as blood tests and tumor imaging studies.
- AT13387 will be given in 28-day cycles of treatment. Participants will receive AT13387
twice a week (2 days in a row) for the first 3 weeks of the cycle, followed by a fourth
week without the drug.
- Participants will have regular blood and urine samples, imaging studies, eye
examinations, and tumor biopsies to monitor the effects of the treatment.
- Participants will continue treatment with AT13387 unless serious side effects develop or
the tumor stops responding to treatment.
Background:
- AT13387 is a synthetic Hsp90 inhibitor that has demonstrated improved characteristics
over other Hsp90 inhibitors. AT13387 has a long tumor retention half-life and prolonged
inhibitory effect on its known oncogenic client proteins.
- AT13387 has demonstrated activity against multiple cancer cell lines and tumor
xenografts in pre-clinical models.
Primary Objectives:
- Define the safety and tolerability of AT13387 administered on a QDx2 every week, 3 weeks
out of 4 scheduled, in adults with refractory solid tumors.
- Establish the maximum tolerated dose (MTD) of AT13387 administered on a QDx2 every week,
3 weeks out of 4 schedule, in adults with refractory solid tumors.
Secondary Objectives:
- Determine the pharmacokinetics (PK) of AT13387 administered on a QDx2 every week, 3
weeks out of 4 schedule, in adults with refractory solid tumors.
- Assess pharmacodynamic (PD) markers of Hsp90 inhibition and modulation of Hsp90 client
proteins by AT13387 in tumor tissue, serum, and PBMCs.
Eligibility:
-Study participants must have histologically confirmed solid tumor malignancy that has
progressed or recurred after at least one line of chemotherapy, or for which no standard
treatment option exists. Participants enrolling in the expansion phase must have disease
amenable to biopsy with willingness to undergo pre- and post-treatment biopsies (Remove the
HER 2 archival tissue).
Study Design:
- This study will follow an accelerated titration design 2B with initial dose levels
increased in 100% increments.
- The accelerated phase ends when one patient experiences a dose-limiting toxicity or two
patients experience Grade 2 drug-related toxicity during the first cycle; when dose
level 3 is reached; or at first instance of Grade 2 ocular toxicity in any cycle.
- AT13387 will be administered intravenously, over 1 hour, on 2 consecutive days, 3 out of
4 weeks, every 28 days (i.e., on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle).
- PK and PD studies will be conducted in cycle 1 only. Once the MTD is established, 10
additional patients, will be entered at the MTD to further define toxicity and perform
PD studies at this dose; pre- and post-treatment tumor biopsies will be mandatory for
these patients.
- CT scans will be performed at baseline and every 2 cycles for restaging.
- Up to 37 patients may be treated.
- Study participants will be offered optional participation in an ongoing NCI imaging
study at baseline with a repeat scan following the last dose of AT13387 in cycle 1.
- AT13387 is a synthetic Hsp90 inhibitor that has demonstrated improved characteristics
over other Hsp90 inhibitors. AT13387 has a long tumor retention half-life and prolonged
inhibitory effect on its known oncogenic client proteins.
- AT13387 has demonstrated activity against multiple cancer cell lines and tumor
xenografts in pre-clinical models.
Primary Objectives:
- Define the safety and tolerability of AT13387 administered on a QDx2 every week, 3 weeks
out of 4 scheduled, in adults with refractory solid tumors.
- Establish the maximum tolerated dose (MTD) of AT13387 administered on a QDx2 every week,
3 weeks out of 4 schedule, in adults with refractory solid tumors.
Secondary Objectives:
- Determine the pharmacokinetics (PK) of AT13387 administered on a QDx2 every week, 3
weeks out of 4 schedule, in adults with refractory solid tumors.
- Assess pharmacodynamic (PD) markers of Hsp90 inhibition and modulation of Hsp90 client
proteins by AT13387 in tumor tissue, serum, and PBMCs.
Eligibility:
-Study participants must have histologically confirmed solid tumor malignancy that has
progressed or recurred after at least one line of chemotherapy, or for which no standard
treatment option exists. Participants enrolling in the expansion phase must have disease
amenable to biopsy with willingness to undergo pre- and post-treatment biopsies (Remove the
HER 2 archival tissue).
Study Design:
- This study will follow an accelerated titration design 2B with initial dose levels
increased in 100% increments.
- The accelerated phase ends when one patient experiences a dose-limiting toxicity or two
patients experience Grade 2 drug-related toxicity during the first cycle; when dose
level 3 is reached; or at first instance of Grade 2 ocular toxicity in any cycle.
- AT13387 will be administered intravenously, over 1 hour, on 2 consecutive days, 3 out of
4 weeks, every 28 days (i.e., on days 1, 2, 8, 9, 15, and 16 of each 28-day cycle).
- PK and PD studies will be conducted in cycle 1 only. Once the MTD is established, 10
additional patients, will be entered at the MTD to further define toxicity and perform
PD studies at this dose; pre- and post-treatment tumor biopsies will be mandatory for
these patients.
- CT scans will be performed at baseline and every 2 cycles for restaging.
- Up to 37 patients may be treated.
- Study participants will be offered optional participation in an ongoing NCI imaging
study at baseline with a repeat scan following the last dose of AT13387 in cycle 1.
- INCLUSION CRITERIA:
- Patients must have histologically documented (confirmed at the Laboratory of
Pathology, NCI) solid tumor malignancy that is metastatic or unresectable, for which
standard curative measures do not exist, or have failed at least one line of standard
therapy.
- Patients must have measurable or evaluable disease.
- Patients must have completed any chemotherapy, radiation therapy, or biologic therapy
greater than or equal to 4 weeks prior to entering the study (6 weeks for nitrosoureas
or mitomycin C).
Patients must be greater than or equal to 2 weeks since any prior administration of a study
drug in an exploratory IND/Phase 0 study. Patients must have recovered to eligibility
levels from prior toxicity or adverse events. Patients receiving bisphosphonates for any
cancer are eligible to participate.
- Age greater than or equal to 18 years. Because no dosing or adverse event data are
currently available on the use of AT13387 in patients < 18 years of age, children are
excluded from this study.
- The Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to
2.
- Life expectancy > 3 months.
- Patients must have normal or adequate organ and marrow function as defined below:
- Absolute neutrophil count greater than or equal to 1,500/microL
- Platelets greater than or equal to 100,000/microL
- Total bilirubin less than or equal to 1.5 times institutional ULN
- AST (SGOT)/ALT (SGPT) less than or equal to 2.5 times institutional ULN
- Creatinine <1.5 times ULN; OR
- Measured creatinine greater than or equal to 60 mL/minute for patients with
clearance creatinine levels greater than or equal to 1.5 times ULN
- The effects of AT13387 on the developing human fetus are unknown. For this reason,
women of childbearing potential and men must agree to use adequate contraception
(hormonal or barrier method of birth control or abstinence) prior to study entry, for
the duration of study participation, and for 2 months after completion of study. Women
of childbearing potential must have a negative pregnancy test within 72 hours of
enrollment 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. Because there is an unknown but potential risk to nursing infants
secondary to treatment of the mother with AT13387, breastfeeding should be
discontinued if the mother is treated with AT13387.
- During the expansion phase of the protocol, patients must have:
- Disease amenable to biopsy
- Willingness to undergo pre- and post-treatment biopsies
- Ability to understand and the willingness to sign a written informed consent document.
- Currently enrolling in the expansion phase. Patients must have:
- Disease amenable to biopsy
- Willingness to undergo pre- and post-treatment biopsies
EXCLUSION CRITERIA:
- Patients with known brain metastases or carcinomatous meningitis are excluded from
this clinical trial, with the exception of patients whose brain metastatic disease
status has remained stable for greater than or equal to 2 months after treatment of
the brain metastases, without steroids or anti-seizure medications. These patients may
be enrolled at the discretion of the principal investigator.
- Patients with clinically significant intercurrent illnesses, including but not limited
to, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled
cardiac arrhythmia, or psychiatric illness/social situations that would limit
compliance with study requirements.
- QTc > 450 msec for men and > 470 msec for women.
- HIV-positive patients on combination antiretroviral therapy are ineligible because of
the potential for PK interactions with AT13387.
- Pregnant women are ineligible because the effects of AT13387 on the developing human
fetus are unknown.
- Exclude patients with active gastrointestinal bleeding or an event of gastrointestinal
bleeding within a week of starting treatment.
INCLUSION OF WOMEN AND MINORITIES:
Both men and women, and members of all races and ethnic groups, are eligible for this
trial.
We found this trial at
1
site
9000 Rockville Pike
Bethesda, Maryland 20892
Bethesda, Maryland 20892
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