Gemcitabine Hydrochloride and Tanespimycin in Treating Patients With Recurrent Advanced Ovarian Epithelial or Peritoneal Cavity Cancer

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00093496
• Collaborator: (none)
• Enrollment: 29
• Location: 1
• Arm: 1
• Duration (Months): 53
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

Phase II trial to study the effectiveness of gemcitabine hydrochloride and tanespimycin in treating patients who have recurrent advanced ovarian epithelial or primary peritoneal cavity cancer. Drugs used in chemotherapy, such as gemcitabine hydrochloride and tanespimycin, work in different ways to stop tumor cells from dividing so they stop growing or die.

Condition or Disease	Intervention/Treatment	Phase
Primary Peritoneal Cavity Cancer; Recurrent Ovarian Epithelial Cancer; Stage III Ovarian Epithelial Cancer; Stage IV Ovarian Epithelial Cancer	Drug: gemcitabine hydrochloride; Drug: tanespimycin	Phase 2

Detailed Description

OBJECTIVES:

1. Determine the response rate, time to progression, and survival of patients with recurrent advanced ovarian epithelial or primary peritoneal cavity cancer treated with gemcitabine hydrochloride and 17-N-allylamino-17-demethoxygeldanamycin (17-AAG) (tanespimycin).

2. Determine the toxicity of this regimen in these patients. III. Correlate the effect of 17-AAG alone on chaperone and client proteins in tumor samples and peripheral blood mononuclear cells with response, time to progression, and survival of these patients.

OUTLINE: This is a multicenter study. Patients are stratified according to gemcitabine hydrochloride therapy (gemcitabine hydrochloride-naive/no prior exposure to gemcitabine hydrochloride vs gemcitabine hydrochloride-resistant/prior exposure to gemcitabine hydrochloride as a single agent with disease progression while on treatment). Patients receive tanespimycin intravenously (IV) over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 29 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase II Trial Of Gemcitabine in Combination With 17-Allylaminogeldamycin (17-AAG) In Advanced Epithelial Ovarian And Primary Peritoneal Carcinoma
• Study Start Date: Oct 1, 2007
• Actual Primary Completion Date: Apr 1, 2010
• Actual Study Completion Date: Mar 1, 2012

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Treatment (chemotherapy) Patients are stratified according to gemcitabine hydrochloride therapy (gemcitabine hydrochloride-naive/no prior exposure to gemcitabine hydrochloride vs gemcitabine hydrochloride-resistant/prior exposure to gemcitabine hydrochloride as a single agent with disease progression while on treatment). Patients receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.

Drug: gemcitabine hydrochloride; Given IV; Other Names: dFdC difluorodeoxycytidine hydrochloride gemcitabine Gemzar ; Drug: tanespimycin; Given IV; Other Names: 17-AAG

Outcome Measures

Primary Outcome Measures

1. Proportion of Patients Who Experience a Confirmed Response According to Modified RECIST Criteria. [Participants were evaluated every 6 weeks on treatment, with median treatment length of 12 weeks (3 week minimum and 42 week maximum).]

   Objective response will be measured using the modified RECIST criteria. A confirmed response requires an objective status of complete or partial response on 2 consecutive evaluations occurring 4 or more weeks apart. Complete Response (CR): Disappearance of all target lesions and normalization of tumor biomarkers. Partial Response (PR): At least a 30% decrease in the sum of the target lesions from the baseline.

Secondary Outcome Measures

1. Times to Progression [Participants were evaluated every 6 weeks on treatment (maximum 42 weeks), and followed up to 5 years from registration.]

   Defined as the time from registration to the date of progression or last follow-up, whichever comes first. Estimated using the method of Kaplan-Meier

2. Overall Survival [Every 3 months until disease progression and then every 6 months for up to 5 years.]

   Defined as the time from registration to date of last follow-up or death due to any cause. Estimated using the method of Kaplan-Meier.

3. Toxicity [Participants were evaluated every 6 weeks on treatment (maximum 42 weeks)]

   Defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as an adverse event classified as either possibly, probably, or definitely related to study treatment. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Diagnosis of ovarian epithelial or primary peritoneal cavity cancer

• Relapsed disease

• Persistent disease

• Platinum-resistant disease, defined as having evidence of disease that would be expected to be non-responsive to additional platinum-containing regimens or contraindication to platinum-based chemotherapy and 1 of the following:

• Failure to obtain a complete response to initial platinum therapy

• Recurrence < 6 months after completing a platinum-containing regimen for initial or recurrent disease

• Any of the above situations and following treatment with additional chemotherapy regimens (e.g., non-platinum containing regimens)

• Relative or absolute contraindication to platinum-based chemotherapy regimens (e.g., platinum allergy) as determine by the investigator

• Measurable or evaluable disease

• Patients with a rising CA 125 level, even in the absence of other indicators of disease, allowed provided CA 125 is ≥ 2 times upper limit of normal (ULN)

• Patients with accessible disease must be willing to undergo tumor biopsies

• No CNS metastases

• Performance status - ECOG 0-2

• WBC ≥ 3,000/mm^3

• Platelet count ≥ 100,000/mm^3

• Hemoglobin ≥ 9.0 g/dL

• Bilirubin normal

• Alkaline phosphatase ≤ 2.5 times ULN

• AST ≤ 2.5 times ULN

• Creatinine ≤ 1.5 times ULN

• Ejection fraction > 40% by ECHO for patients with prior anthracycline therapy

• No significant cardiac disease including any of the following:

• New York Heart Association class III or IV heart disease

• History of myocardial infraction within the past year

• Uncontrolled dysrhythmias or requirement for antiarrhythmic drugs

• Poorly controlled angina

• No history of serious ventricular arrhythmia (i.e., ventricular tachycardia or ventricular fibrillation ≥ 3 beats in a row)

• No history of QTc ≥ 500 msec

• No active ischemic heart disease within the past 12 months

• No congenital long QT syndrome

• No left bundle branch block

• No cardiac symptoms ≥ grade 2

• No history of cardiac toxicity after receiving anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone, bleomycin, or carmustine)

• Does not meet the medicare criteria for home oxygen

• No pulse oximetry at rest and exercise < 88%

• No symptomatic pulmonary disease requiring medication including any of the following:

• Dyspnea on or off exertion

• Paroxysmal nocturnal dyspnea

• Oxygen requirement

• Significant pulmonary disease (e.g., chronic obstructive/restrictive pulmonary disease)

• No pulmonary symptoms ≥ grade 2

• No history of pulmonary toxicity after receiving anthracyclines (e.g., doxorubicin hydrochloride, daunorubicin hydrochloride, mitoxantrone, bleomycin, or carmustine)

• K+, Mg ++, and Ca ++ normal

• No seizure disorder

• No uncontrolled infection

• No history of serious allergic reaction to eggs

• More than 4 weeks since prior immunotherapy

• More than 4 weeks since prior biologic therapy

• No concurrent immunotherapy

• No concurrent routine or prophylactic colony-stimulating factors (e.g., filgrastim [G-CSF] or sargramostim [GM-CSF])

• See Disease Characteristics

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

• Prior gemcitabine hydrochloride allowed provided 1 of the following criteria is met:

• Patients have no prior exposure to gemcitabine hydrochloride

• Patients who have prior exposure to gemcitabine hydrochloride as a single agent have experienced progressive disease while on treatment

• No other concurrent chemotherapy

• No prior radiotherapy to > 25% of bone marrow

• No history of radiotherapy that potentially included the heart in the field (e.g., mantle)

• Chest wall irradiation or other radiotherapy techniques that do not include the heart in the radiation field area allowed

• More than 4 weeks since prior radiotherapy

• More than 4 weeks since prior radiopharmaceuticals

• No concurrent radiotherapy

• No other concurrent investigational therapy

• No concurrent medications that may prolong QTc

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic	Rochester	Minnesota	United States	55905

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Paul Haluska, Mayo Clinic

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00093496
• Other Study ID Numbers: NCI-2009-00052; NCI-2009-00052; CDR0000388036; NCI-6307; MAYO-MC0362; MC0362; 6307; P30CA015083; N01CM62205; NCT01646918; NCT01664312
• First Posted: Oct 8, 2004
• Last Update Posted: May 20, 2014
• Last Verified: Oct 1, 2011

• Additional relevant MeSH terms: Carcinoma, Ovarian Epithelial; Peritoneal Neoplasms; Gemcitabine

Study Results

Participant Flow

Recruitment Details	Twenty-nine patients were enrolled between November 15, 2007 and October 29, 2009. Two participants were found to be ineligible and two participants had major protocol violations. Therefore, we summarize baseline characteristics and adverse events using all 29 patients, but report endpoint analyses using 25 participants.
Pre-assignment Detail	Participants were divided into two groups according to their prior gemcitabine exposure. Cohort 1 participants had no prior exposure to gemcitabine. Cohort 2 was comprised of participants with prior exposure to gemcitabine as a single agent or had experienced disease progression while on gemcitabine therapy.

Arm/Group Title	Cohort 1 (No Prior Gemcitabine Exposure)	Cohort 2 (Prior Gemcitabine Exposure)
Arm/Group Description	Patients with no prior gemcitabine exposure receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.	Patients with prior gemcitabine exposure receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.
Period Title: Overall Study
STARTED	15	14
COMPLETED	14	11
NOT COMPLETED	1	3

Baseline Characteristics

Arm/Group Title	Cohort 1 (No Prior Gemcitabine Exposure)	Cohort 2 (Prior Gemcitabine Exposure)	Total
Arm/Group Description	Patients with no prior gemcitabine exposure receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.	Patients with prior gemcitabine exposure receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.	Total of all reporting groups
Overall Participants	15	14	29
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	64	63.5	64
Sex: Female, Male (Count of Participants)
Female	15 100%	14 100%	29 100%
Male	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	15 100%	14 100%	29 100%

Outcome Measures

1. Primary Outcome

Title	Proportion of Patients Who Experience a Confirmed Response According to Modified RECIST Criteria.
Description	Objective response will be measured using the modified RECIST criteria. A confirmed response requires an objective status of complete or partial response on 2 consecutive evaluations occurring 4 or more weeks apart. Complete Response (CR): Disappearance of all target lesions and normalization of tumor biomarkers. Partial Response (PR): At least a 30% decrease in the sum of the target lesions from the baseline.
Time Frame	Participants were evaluated every 6 weeks on treatment, with median treatment length of 12 weeks (3 week minimum and 42 week maximum).

Outcome Measure Data

Analysis Population Description

In Cohort 1, one patient was found to be ineligible. In Cohort 2, one patient was ineligible and two patients had protocol violations. Therefore, 14 participants in Cohort 1 and eleven participants in Cohort 2 were analyzed for the primary endpoint.

Arm/Group Title	Cohort 1 (No Prior Gemcitabine Exposure)	Cohort 2 (Prior Gemcitabine Exposure)
Arm/Group Description	Patients with no prior gemcitabine exposure receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.	Patients with prior gemcitabine exposure receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.
Measure Participants	14	11
Confirmed Partial Response (PR)	0.071 0.5%	0 0%
Confirmed Complete Response (CR)	0 0%	0 0%

2. Secondary Outcome

Title	Times to Progression
Description	Defined as the time from registration to the date of progression or last follow-up, whichever comes first. Estimated using the method of Kaplan-Meier
Time Frame	Participants were evaluated every 6 weeks on treatment (maximum 42 weeks), and followed up to 5 years from registration.

Outcome Measure Data

Analysis Population Description

An interim analysis was done on the first 12 eligible participants in each cohort. Due to drug shortage and lack of clinical activity, the interim analysis for Cohort 2 was conducted on the first 11 participants.

Arm/Group Title	Cohort 1 (No Prior Gemcitabine Exposure)	Cohort 2 (Prior Gemcitabine Exposure)
Arm/Group Description	Patients with no prior gemcitabine exposure receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.	Patients with prior gemcitabine exposure receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.
Measure Participants	12	11
Median (95% Confidence Interval) [months]	1.6	2.7

3. Secondary Outcome

Title	Overall Survival
Description	Defined as the time from registration to date of last follow-up or death due to any cause. Estimated using the method of Kaplan-Meier.
Time Frame	Every 3 months until disease progression and then every 6 months for up to 5 years.

Outcome Measure Data

Analysis Population Description

An interim analysis was done on the first 12 eligible participants in each cohort. Due to drug shortage and lack of clinical acttivity, the interim analysis for Cohort 2 was conducted on the first 11 participants.

Arm/Group Title	Cohort 1 (No Prior Gemcitabine Exposure)	Cohort 2 (Prior Gemcitabine Exposure)
Arm/Group Description	Patients with no prior gemcitabine exposure receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.	Patients with prior gemcitabine exposure receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.
Measure Participants	12	11
Median (95% Confidence Interval) [months]	18.3	11.5

4. Secondary Outcome

Title	Toxicity
Description	Defined by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 as an adverse event classified as either possibly, probably, or definitely related to study treatment. The maximum grade for each type of toxicity will be recorded for each patient, and frequency tables will be reviewed to determine toxicity patterns.
Time Frame	Participants were evaluated every 6 weeks on treatment (maximum 42 weeks)

Outcome Measure Data

Analysis Population Description

In Cohort 1, one patient was found to be ineligible. In Cohort 2, one patient was ineligible and two patients had protocol violations. Therefore, 14 participants in Cohort 1 and eleven participants in Cohort 2 were analyzed for adverse events.

Arm/Group Title	Cohort 1 (No Prior Gemcitabine Exposure)	Cohort 2 (Prior Gemcitabine Exposure)
Arm/Group Description	Patients with no prior gemcitabine exposure receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.	Patients with prior gemcitabine exposure receive tanespimycin IV over 2 hours on days 1 and 8 during course 1 and days 2 and 9 during subsequent courses and gemcitabine hydrochloride IV over 30 minutes on day 7 during course 1 and days 1 and 8 during subsequent courses. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity. Patients are followed every 3 months until disease progression and then every 6 months for up to 5 years.
Measure Participants	14	11
Grade 3	9	7
Grade 4 or Higher	0	0

Adverse Events

Arm/Group Title	All Patients Receiving Gemcitabine
Arm/Group Description	All patients receiving gemcitabine were combined to analyze toxicity.
All Cause Mortality
	All Patients Receiving Gemcitabine
	Affected / at Risk (%)	# Events
Total	/ (NaN)
Serious Adverse Events
	All Patients Receiving Gemcitabine
	Affected / at Risk (%)	# Events
Total	10/29 (34.5%)
Blood and lymphatic system disorders
Hemoglobin decreased	1/29 (3.4%)	1
Gastrointestinal disorders
Abdominal pain	1/29 (3.4%)	1
Nausea	2/29 (6.9%)	5
Small intestinal obstruction	1/29 (3.4%)	2
Vomiting	2/29 (6.9%)	2
General disorders
Edema limbs	1/29 (3.4%)	1
Infections and infestations
Urinary tract infection	2/29 (6.9%)	2
Investigations
Alkaline phosphatase increased	1/29 (3.4%)	1
Aspartate aminotransferase increased	1/29 (3.4%)	1
Creatinine increased	1/29 (3.4%)	1
Leukocyte count decreased	1/29 (3.4%)	1
Neutrophil count decreased	3/29 (10.3%)	5
Nervous system disorders
Headache	1/29 (3.4%)	1
Peripheral sensory neuropathy	1/29 (3.4%)	1
Skin and subcutaneous tissue disorders
Rash desquamating	1/29 (3.4%)	1
Other (Not Including Serious) Adverse Events
	All Patients Receiving Gemcitabine
	Affected / at Risk (%)	# Events
Total	28/29 (96.6%)
Blood and lymphatic system disorders
Hemoglobin decreased	24/29 (82.8%)	79
Gastrointestinal disorders
Abdominal pain	3/29 (10.3%)	6
Constipation	3/29 (10.3%)	8
Diarrhea	9/29 (31%)	15
Flatulence	1/29 (3.4%)	1
Gastric ulcer	1/29 (3.4%)	1
Nausea	16/29 (55.2%)	26
Stomach pain	1/29 (3.4%)	3
Vomiting	10/29 (34.5%)	13
General disorders
Edema limbs	1/29 (3.4%)	3
Fatigue	7/29 (24.1%)	19
Injury, poisoning and procedural complications
Dermatitis radiation	1/29 (3.4%)	1
Investigations
Alkaline phosphatase increased	6/29 (20.7%)	9
Aspartate aminotransferase increased	8/29 (27.6%)	12
Leukocyte count decreased	14/29 (48.3%)	29
Neutrophil count decreased	17/29 (58.6%)	33
Platelet count decreased	9/29 (31%)	22
Metabolism and nutrition disorders
Anorexia	4/29 (13.8%)	9
Nervous system disorders
Dizziness	2/29 (6.9%)	2
Peripheral motor neuropathy	1/29 (3.4%)	1
Peripheral sensory neuropathy	3/29 (10.3%)	3
Respiratory, thoracic and mediastinal disorders
Cough	8/29 (27.6%)	15
Dyspnea	4/29 (13.8%)	7
Skin and subcutaneous tissue disorders
Alopecia	5/29 (17.2%)	10
Nail disorder	1/29 (3.4%)	3
Rash desquamating	1/29 (3.4%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.