GANNET53: Ganetespib in Metastatic, p53-mutant, Platinum-resistant Ovarian Cancer

• Sponsor: Medical University Innsbruck (Other)
• Overall Status: Terminated
• CT.gov ID: NCT02012192
• Collaborator: European Commission (Other)
• Enrollment: 133
• Locations: 10
• Arms: 2
• Actual Duration (Months): 41
• Patients Per Site: 13.3
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Epithelial ovarian cancer (EOC) is the most lethal gynaecological malignancy causing 41900 deaths annually in Europe. The predominance of aggressive Type II tumours, which are characterised by a high frequency of p53 mutations, and primary or acquired resistance to platinum-based chemotherapy profoundly contribute to the high mortality rate. With current standard therapy the median overall survival of metastatic platinum-resistant (Pt-R) ovarian cancer patients is only 14 month. There is a pressing need for more effective, innovative treatment strategies to particularly improve survival in this subgroup of EOC patients. This is a drug strategy targeting a central driver of tumour aggressiveness and metastatic ability, namely mutant p53, via an innovative new Hsp90 (heat shock protein 90) inhibition mechanism. The most advanced, second-generation Hsp90 inhibitor will be used, Ganetespib. The first part (Phase I) of the GANNET53 trial will test the safety of Ganetespib in a new combination with standard chemotherapy (Paclitaxel weekly) in Pt-R EOC patients. The second part (randomised Phase II) will examine the efficacy of Ganetespib in combination with standard chemotherapy versus standard chemotherapy alone in EOC patients with Pt-R tumours.

Condition or Disease	Intervention/Treatment	Phase
Epithelial Ovarian Cancer; Fallopian Tube Cancer; Primary Peritoneal Cancer	Drug: Ganetespib; Drug: Paclitaxel	Phase 1/Phase 2

Study Design

• Study Type: Interventional
• Actual Enrollment: 133 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Two-part, Multicentre, International Phase I and II Trial Assessing the Safety and Efficacy of the Hsp90 Inhibitor Ganetespib in Combination With Paclitaxel Weekly in Women With High-grade Serous, High-grade Endometrioid, or Undifferentiated, Platinum-resistant Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer
• Actual Study Start Date: Jul 4, 2014
• Actual Primary Completion Date: Nov 30, 2017
• Actual Study Completion Date: Dec 4, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Ganetespib + Paclitaxel Drug: ganetespib, dose will depend on phase I results, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle); Drug: paclitaxel, 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression.	Drug: Ganetespib; Drug: Paclitaxel
Active Comparator: Paclitaxel Drug: paclitaxel: 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression	Drug: Paclitaxel

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [Time until progression (median w/o new drug 4 months)]

   evaluate the efficacy of ganetespib in combination with weekly paclitaxel compared to weekly paclitaxel alone as measured by Progression-free survival (PFS). Response or progression will be evaluated in this study according to Response Evaluation Criteria In Solid Tumors Criteria version 1.1., CA-125 according to published GCIG criteria, and by the investigator on the basis of physical and/or gynaecological examinations.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Ability to understand and willingness to sign and date a written informed consent document

• Female patients ≥18 years of age

• High-grade serous, high-grade endometrioid, or undifferentiated epithelial ovarian, fallopian tube or primary peritoneal cancer

• Patients in part II: High-grade serous, high-grade endometrioid, or undifferentiated epithelial ovarian, fallopian tube or primary peritoneal cancer confirmed by central histopathology through archival formalin-fixed paraffin embedded (FFPE) or fresh-frozen tumour samples.

• Platinum-resistant disease:

• primary platinum-resistant disease: progression > 1 month and ≤ 6 months after completion of primary platinum-based therapy

• secondary platinum-resistant disease (including secondary platinum-refractory disease): progression ≤ 6 months after (or during) reiterative platinum-based therapy

• Patients must have disease that is measurable according to RECIST 1.1 or assessable according to the GCIG (Eastern Cooperative Oncology Group) CA-125 criteria

• ECOG performance status of 0-1

• Life expectancy of at least 3 months as assessed by the investigator

Adequate function of the bone marrow:

• Platelets ≥100 x 109/L

• Absolute neutrophil count (ANC) ≥ 1.5 x 109/L

• Haemoglobin ≥ 8.5 g/dl. Patients may receive blood transfusion(s) to maintain haemoglobin values > 8.5 g/dl.

Adequate organ functions:

• Creatinine < 2 mg/dl (<177 µmol/L)

• Total bilirubin ≤ 1.5 x upper limit of normal

• SGOT ( serum glutamate oxaloacetate transaminase)/SGPT (serum glutamate pyruvate transaminase) (AST/ALT) ≤ 3 x upper limit of normal

• Urinanalysis or urine dipstick for proteinuria less than 2+. Patients with ≥ 2+ on dipstick should undergo 24-hour urine collection and must demonstrate < 1 g of protein/24 hours. Alternatively, proteinuria testing can be performed according to local standards

• Negative urine/serum pregnancy test in women of childbearing potential (WOCBP, see section 5). WOCBP who are sexually active, agree to use highly effective means of contraception during the study and for at least 6 months post-study treatment. Allowed are accepted and effective non-hormonal methods of contraception and sexual abstinence or vasectomised partners (>3 months previously). Vasectomy has to be confirmed by two negative semen analyses.

• Availability of archival ovarian cancer tissue for central histopathological review and p53 mutational analysis

Exclusion Criteria:

• Ovarian tumours with low malignant potential (i.e. borderline tumours)

• Primary platinum-refractory disease (progression during primary platinum-based chemotherapy)

PRIOR, CURRENT OR PLANNED TREATMENT:

• Previous treatment with > 2 chemotherapy regimens in the platinum-resistant setting (excluding targeted and endocrine therapies).

• More than 4 previous lines of chemotherapy.

• Major surgery within 2 weeks prior to first dose of ganetespib

PRIOR OR CONCOMITANT CONDITIONS OR PROCEDURES:

• Patients with a history of prior malignancies, except, disease-free time-frame of ≥ 3 years prior to randomisation.

• Patients with prior in-situ carcinomas, except:

complete removal of the tumour is given

• Known history of severe (grade 3 or 4) allergic or hypersensitivity reactions to excipients (e.g., polyethylene glycol [PEG] 300 and Polysorbate 80)

• History of intolerance or hypersensitivity to paclitaxel and/or adverse events related to paclitaxel that resulted in paclitaxel being permanently discontinued

• Peripheral neuropathy of grade > 2 per NCI CTCAE (Common Toxicity Criteria for Adverse Effects), version 4.03, within 4 weeks prior to randomisation

• Clinical symptomatic bowel obstruction at time of screening

• Left ventricular ejection fraction defined by MUGA (multigated acquisition)/ECHO below the institutional lower limit of normal

• Patients with symptomatic brain metastases

• Significant cardiac disease: New York Heart Association (NYHA) Class 3 or 4; myocardial infarction within the past 6 months; unstable angina; coronary angioplasty or coronary artery bypass graft (CABG) within the past 6 month; or uncontrolled atrial or ventricular cardiac arrhythmias.

• History of prolonged QT syndrome, or family member with prolonged QT syndrome

• QTc (corrected QT interval) interval > 470 msec when 3 consecutive EKG values are averaged

• Ventricular tachycardia or a supraventricular tachycardia that requires treatment with a Class Ia antiarrhythmic drug (e.g., quinidine, procainamide, disopyramide) or Class III antiarrhythmic drug (e.g., sotalol, amiodarone, dofetilide). Use of other antiarrhythmic drugs is permitted

• Second- or third-degree atrioventricular (AV) block, except:

treated with a permanent pacemaker

• Complete left bundle branch block (LBBB)

• Any other condition that, in the opinion of the investigator, may compromise the safety, compliance of the patient, or would preclude the patient from successful completion of the study.

• Participation in another clinical study with experimental therapy within 28 days before start of treatment.

• Women who are pregnant or are lactating

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Medical University Innsbruck, Department for Gynaecology and Obstetrics	Innsbruck		Austria	6020
2	Katholieke Universiteit Leuven, Dept. of Gynaecologic Oncology	Leuven		Belgium	3000
3	Centre de lutte contre le cancer Francois Baclesse	Caen		France	14076
4	Centre Anticancereux Léon Bérard	Lyon		France	69373
5	Assistance Publique - Hôpitaux de Paris Medical Oncology Department	Paris		France	45004
6	Universitätsmedizin Berlin Charité, Dept. for Gynecology	Berlin		Germany	10117
7	University Hospital Carl Gustav Carus Dresden, Department of Gynaecology and Obstetrics	Dresden		Germany	01069
8	Kliniken Essen Mitte, Evang. Huyssens-Stiftung / Knappschaft GmbH Department of Gynaecologic Oncology	Essen		Germany	45136
9	Universitätsklinikum Hamburg-Eppendorf Dept. of Gynecology and Gynecologic Oncology	Hamburg		Germany	20246
10	Otto-von-Guericke-Universität Magdeburg	Magdeburg		Germany	39106

Sponsors and Collaborators

• Medical University Innsbruck
• European Commission

Investigators

• Principal Investigator: Nicole Concin, MD, Medical University Innsbruck

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Feb 18, 2016

More Information

Publications

None provided.

• Responsible Party: Nicole Concin, Univ.-Prof. Dr., Medical University Innsbruck
• ClinicalTrials.gov Identifier: NCT02012192
• Other Study ID Numbers: GANNET53; 2013-003868-31
• First Posted: Dec 16, 2013
• Last Update Posted: Aug 13, 2019
• Last Verified: Jun 1, 2019

• Keywords provided by Nicole Concin, Univ.-Prof. Dr., Medical University Innsbruck: High-grade serous; high-grade endometrioid; undifferentiated
• Additional relevant MeSH terms: Ovarian Neoplasms; Carcinoma, Ovarian Epithelial; Fallopian Tube Neoplasms; Paclitaxel

Study Results

Participant Flow

Arm/Group Title	Ganetespib + Paclitaxel	Paclitaxel
Arm/Group Description	Drug: ganetespib, 150 mg/m², given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle); Drug: paclitaxel, 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression. Ganetespib Paclitaxel	Drug: paclitaxel: 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression Paclitaxel
Period Title: Overall Study
STARTED	90	43
COMPLETED	63	43
NOT COMPLETED	27	0

Baseline Characteristics

Arm/Group Title	Ganetespib + Paclitaxel	Paclitaxel	Total
Arm/Group Description	Drug: ganetespib, 150 mg/m², given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle); Drug: paclitaxel, 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression.	Drug: paclitaxel: 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression	Total of all reporting groups
Overall Participants	90	43	133
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	57 63.3%	25 58.1%	82 61.7%
>=65 years	33 36.7%	18 41.9%	51 38.3%
Sex: Female, Male (Count of Participants)
Female	90 100%	43 100%	133 100%
Male	0 0%	0 0%	0 0%
Race/Ethnicity, Customized (Count of Participants)
White	66 73.3%	31 72.1%	97 72.9%
Black	0 0%	0 0%	0 0%
Asian	1 1.1%	0 0%	1 0.8%
Privacy	23 25.6%	12 27.9%	35 26.3%
Region of Enrollment (participants) [Number]
Austria	1 1.1%	1 2.3%	2 1.5%
Belgium	20 22.2%	10 23.3%	30 22.6%
France	37 41.1%	17 39.5%	54 40.6%
Germany	32 35.6%	15 34.9%	47 35.3%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	evaluate the efficacy of ganetespib in combination with weekly paclitaxel compared to weekly paclitaxel alone as measured by Progression-free survival (PFS). Response or progression will be evaluated in this study according to Response Evaluation Criteria In Solid Tumors Criteria version 1.1., CA-125 according to published GCIG criteria, and by the investigator on the basis of physical and/or gynaecological examinations.
Time Frame	Time until progression (median w/o new drug 4 months)

Outcome Measure Data

Analysis Population Description

ITT population

Arm/Group Title	Ganetespib + Paclitaxel	Paclitaxel
Arm/Group Description	Drug: ganetespib, 150 mg/m², given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle); Drug: paclitaxel, 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression.	Drug: paclitaxel: 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression
Measure Participants	90	43
Median (95% Confidence Interval) [months]	3.5	5.3

Adverse Events

Time Frame	After informed consent has been obtained but prior to initiation of the study drug, only SAEs considered to be related to a protocol-mandated intervention were reported. After initiation of study drug, all AEs and SAEs regardless of relationship to the study drug, will be reported until safety follow-up at 28 days after the last dose of IMP or EOT or until the event has resolved to baseline grade or better.
Adverse Event Reporting Description	An AE is any untoward adverse change from the subject's baseline condition, i.e. any unfavourable and unintended sign including an abnormal laboratory finding, symptom or disease which is considered to be clinically relevant by the physician that occurs during the course of the study, whether or not considered related to the study drug. All AEs collected during the course of the trial (from the time of informed consent until EOT as described above) have been reported here.
Arm/Group Title	Ganetespib + Paclitaxel		Paclitaxel
Arm/Group Description	Drug: ganetespib, 150 mg/m², given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle); Drug: paclitaxel, 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression.		Drug: paclitaxel: 80 mg/m2, given iv once weekly for 3 out of 4 weeks (days 1, 8, 15 of each 4-weeks/28-days cycle), until progression
All Cause Mortality
	Ganetespib + Paclitaxel		Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	66/90 (73.3%)		29/43 (67.4%)
Serious Adverse Events
	Ganetespib + Paclitaxel		Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	34/90 (37.8%)		10/43 (23.3%)
Blood and lymphatic system disorders
Anemia	1/90 (1.1%)		0/43 (0%)
febrile neutropenia	1/90 (1.1%)		0/43 (0%)
Hypovolemia	1/90 (1.1%)		0/43 (0%)
Gastrointestinal disorders
Abdominal distention	1/90 (1.1%)		0/43 (0%)
Abdominal pain	3/90 (3.3%)		1/43 (2.3%)
Anal hemorrhage	0/90 (0%)		1/43 (2.3%)
Diarrhea	3/90 (3.3%)		0/43 (0%)
Esophagitis	1/90 (1.1%)		0/43 (0%)
Ileus	2/90 (2.2%)		1/43 (2.3%)
Rectal Ulcer	1/90 (1.1%)		0/43 (0%)
Small intestinal obstruction	8/90 (8.9%)		1/43 (2.3%)
Small intestinal perforation	2/90 (2.2%)		0/43 (0%)
Subileus	1/90 (1.1%)		0/43 (0%)
Subobstruction colon	1/90 (1.1%)		0/43 (0%)
Vomiting	1/90 (1.1%)		2/43 (4.7%)
General disorders
Fever	1/90 (1.1%)		1/43 (2.3%)
General physical health deterioration	2/90 (2.2%)		1/43 (2.3%)
Infusion site extravasation	0/90 (0%)		1/43 (2.3%)
Sudden death NOS	1/90 (1.1%)		0/43 (0%)
Hepatobiliary disorders
Hemobilia	1/90 (1.1%)		0/43 (0%)
Hepatic failure	1/90 (1.1%)		0/43 (0%)
Icterus	1/90 (1.1%)		0/43 (0%)
Infections and infestations
Sepsis	6/90 (6.7%)		0/43 (0%)
Urinary tract infection	5/90 (5.6%)		1/43 (2.3%)
Erysipelas	0/90 (0%)		3/43 (7%)
Catheter related infection	1/90 (1.1%)		0/43 (0%)
Urethral infection	1/90 (1.1%)		0/43 (0%)
Infection NOS	0/90 (0%)		1/43 (2.3%)
Injury, poisoning and procedural complications
Rupture of renal pelvis	1/90 (1.1%)		0/43 (0%)
Vascular access complication	0/90 (0%)		1/43 (2.3%)
Metabolism and nutrition disorders
Anorexia	1/90 (1.1%)		0/43 (0%)
Hyperptassemia	1/90 (1.1%)		0/43 (0%)
Hypokalemia	1/90 (1.1%)		0/43 (0%)
Nervous system disorders
Visual acuity reduced	1/90 (1.1%)		0/43 (0%)
Renal and urinary disorders
Acute kidney injury	1/90 (1.1%)		0/43 (0%)
Cystitis	1/90 (1.1%)		0/43 (0%)
Kidney insufficiency	1/90 (1.1%)		0/43 (0%)
Renal disorders NEC	1/90 (1.1%)		0/43 (0%)
Urinary tract obstruction	0/90 (0%)		2/43 (4.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/90 (1.1%)		0/43 (0%)
Pleural effusion	1/90 (1.1%)		0/43 (0%)
Respiratory failure	1/90 (1.1%)		0/43 (0%)
Vascular disorders
Deep vein thrombosis	0/90 (0%)		1/43 (2.3%)
Thromboemblic events	1/90 (1.1%)		0/43 (0%)
Other (Not Including Serious) Adverse Events
	Ganetespib + Paclitaxel		Paclitaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	88/90 (97.8%)		41/43 (95.3%)
Blood and lymphatic system disorders
Anemia	56/90 (62.2%)		27/43 (62.8%)
Thrombocytopenia	7/90 (7.8%)		0/43 (0%)	0
Gastrointestinal disorders
Abdominal pain	31/90 (34.4%)		12/43 (27.9%)
Abdominal distention	8/90 (8.9%)		2/43 (4.7%)
Constipation	21/90 (23.3%)		9/43 (20.9%)
Diarrhea	73/90 (81.1%)		15/43 (34.9%)
Dry mouth	6/90 (6.7%)		2/43 (4.7%)
Dyspepsia	0/90 (0%)		3/43 (7%)
Gastroesophageal reflux disease	6/90 (6.7%)		2/43 (4.7%)
Mucositis oral	5/90 (5.6%)		0/43 (0%)
Nausea	41/90 (45.6%)		21/43 (48.8%)
Vomiting	29/90 (32.2%)		9/43 (20.9%)
General disorders
Astenia	22/90 (24.4%)		11/43 (25.6%)
Edema limbs	7/90 (7.8%)		4/43 (9.3%)
Edema peripheral	6/90 (6.7%)		7/43 (16.3%)
Fatigue	26/90 (28.9%)		8/43 (18.6%)
Fever	10/90 (11.1%)		0/43 (0%)
Malaise	0/90 (0%)		3/43 (7%)
Mucosal inflammation	5/90 (5.6%)		0/43 (0%)
Immune system disorders
Allergic reaction	5/90 (5.6%)		3/43 (7%)
Infections and infestations
Bronchial infection	5/90 (5.6%)		0/43 (0%)
Urinary tract infection	8/90 (8.9%)		6/43 (14%)
Investigations
Alanine aminotransferase increased	0/90 (0%)		2/43 (4.7%)
Aspartate aminotransferase increased	0/90 (0%)		3/43 (7%)
Electrocardiogram QT corrected intervall prolonged	13/90 (14.4%)		0/43 (0%)
Lymphocyte count decreased	9/90 (10%)		4/43 (9.3%)
Neutrophil count decreased	26/90 (28.9%)		10/43 (23.3%)
Weight loss	9/90 (10%)		0/43 (0%)
White blood cells decreased	13/90 (14.4%)		6/43 (14%)
Metabolism and nutrition disorders
Anorexia	18/90 (20%)		6/43 (14%)
Hypokalaemia	7/90 (7.8%)		3/43 (7%)
Musculoskeletal and connective tissue disorders
Anthralgia	0/90 (0%)		2/43 (4.7%)
Back pain	9/90 (10%)		4/43 (9.3%)
Muscle spasms	11/90 (12.2%)		2/43 (4.7%)
Myalgia	0/90 (0%)		3/43 (7%)
Pain in extremity	9/90 (10%)		3/43 (7%)
Nervous system disorders
Dizziness	0/90 (0%)		2/43 (4.7%)
Dysgeusia	5/90 (5.6%)		5/43 (11.6%)
Headache	10/90 (11.1%)		2/43 (4.7%)
Neuropath peripheral	35/90 (38.9%)		21/43 (48.8%)
Paresthesia	0/90 (0%)		3/43 (7%)
Psychiatric disorders
Insomnia	16/90 (17.8%)		4/43 (9.3%)
Renal and urinary disorders
Cystitis non-infective	0/90 (0%)		3/43 (7%)
Respiratory, thoracic and mediastinal disorders
Common cold	0/90 (0%)		3/43 (7%)
Cough	5/90 (5.6%)		3/43 (7%)
Dyspnea	13/90 (14.4%)		9/43 (20.9%)
Epistaxis	5/90 (5.6%)		2/43 (4.7%)
Skin and subcutaneous tissue disorders
Alopecia	35/90 (38.9%)		14/43 (32.6%)
Dry skin	8/90 (8.9%)		0/43 (0%)
Erythema	0/90 (0%)		5/43 (11.6%)
Pruritus	7/90 (7.8%)		2/43 (4.7%)
Rash	5/90 (5.6%)		4/43 (9.3%)
Nail infection NOS	0/90 (0%)		2/43 (4.7%)
Vascular disorders
Flushing	0/90 (0%)		3/43 (7%)
Hot flashes	0/90 (0%)		2/43 (4.7%)
Hypotension	5/90 (5.6%)		0/43 (0%)
Lymphedema	5/90 (5.6%)		2/43 (4.7%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.