Trial on Trabectedin (ET-743) vs Clinician's Choice Chemotherapy in Recurrent Ovarian, Primary Peritoneal or Fallopian Tube Cancers of BRCA Mutated or BRCAness Phenotype Patients (MITO23)

• ClinicalTrials.gov Identifier: NCT02903004
• Recruitment Status: Completed
• First Posted: September 16, 2016
• Last Update Posted: August 25, 2021
• Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Information provided by (Responsible Party): Fondazione Policlinico Universitario Agostino Gemelli IRCCS

Tracking Information

• First Submitted Date: August 26, 2016
• First Posted Date: September 16, 2016
• Last Update Posted Date: August 25, 2021
• Actual Study Start Date: April 11, 2016
• Actual Primary Completion Date: December 20, 2018 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 12, 2016)

Overall Survival (OS) [ Time Frame: 4 years ]

The primary objective is to compare the Trabectedin versus physician' choice chemotherapy in terms of overall survival (OS).

• Original Primary Outcome Measures: Same as current

Current Secondary Outcome Measures (submitted: September 12, 2016)

• Progression free survival (PFS) [ Time Frame: 4 years ]
  Progression-free survival [the diagnosis of progression will be assessed by radiological criteria; CA 125 increases alone (GCIG criteria of progression) will not be considered as progression of disease without a radiological confirmation of progression].
• Duration of Response [ Time Frame: 4 years ]
  Duration of response
• Adverse events [ Time Frame: 4 years ]
  Incidence of adverse events, according to the National Cancer Institute Common Toxicity Criteria (NCI-CTC) version 4.0.

• Original Secondary Outcome Measures: Same as current
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Trial on Trabectedin (ET-743) vs Clinician's Choice Chemotherapy in Recurrent Ovarian, Primary Peritoneal or Fallopian Tube Cancers of BRCA Mutated or BRCAness Phenotype Patients
• Official Title: Randomized Phase III Trial on Trabectedin (ET-743) vs Clinician's Choice Chemotherapy in Recurrent Ovarian, Primary Peritoneal or Fallopian Tube Cancers of BRCA Mutated or BRCAness Phenotype Patients

Brief Summary

This is an open-label, prospective, multicenter, randomized Phase III, clinical trial evaluating the efficacy and safety of trabectedin in BRCA1 and BRCA2 mutation carrier and BRCAness phenotype advanced ovarian cancer patients in comparison to physician' choice chemotherapy.

Arm A: Trabectedin 1.3 mg/mq d1 q 21 in 3 hours (central line) Arm B: Pegylated Liposomal Doxorubicin 40 mg/mq q 28 or Topotecan 4 mg/mq dd 1,8,15 q 28 or Gemcitabine 1000 mg/mq dd 1, 8, 15 q 28 Weekly Paclitaxel 80 mg/mq gg 1, 8, 15 q 28 Carboplatin AUC 5-6 q 21 or 28

Patients will be randomly assigned in a 1:1 ratio to treatment arms. During the randomization process, patients will be stratified by

• Platinum sensitivity
• Measurable disease
• Number of previous chemotherapy lines > vs < 3
• BRCA mutational status

Detailed Description

Subjects will be randomized in a 1:1 ratio to receive one of the following treatments: Arm A: Trabectedin 1.3 mg/m2 d1 q 21 in 3 hours (central line) Arm B: Pegylated Liposomal Doxorubicin 40 mg/mq q 28 or Topotecan 4 mg/ m2 dd 1,8,15 q 28 or Gemcitabine 1000 mg/mq dd 1, 8, 15 q 28 Weekly Paclitaxel 80 mg/ m2 dd 1, 8, 15 q 28 Carboplatin AUC 5-6 q 21 or 28 Randomization will be stratified based on platinum-free interval (PFI) (PFI ≥ 0 and ≤ 6 months vs. PFI > 6 months), presence / absence of measurable disease/number of previous chemotherapy lines, germline BRCA mutational status vs BRCAness phenotype.

Platinum-free interval (PFI) is defined as the time from the last dose of the platinum containing regimen until the first date progression.

Subjects will continue to receive chemotherapy treatment until disease progression (clinical progression meant as global deterioration in health status attributable to the disease requiring a change in therapy without objective evidence of progression is considered progression of disease), intolerability, patient refusal, investigator decision or death from any cause.

Subjects will be evaluated every 12 weeks ± 1 week by Response Evaluation Criteria in Solid Tumors (RECIST 1.1) for objective radiographic response and radiographic disease progression.

• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Ovarian Neoplasms

Intervention

• Drug: Trabectedin
  Other Name: Yondelis
• Drug: Pegylated Liposomal Doxorubicin
• Drug: Topotecan
• Drug: Gemcitabine
• Drug: Weekly Paclitaxel
• Drug: Carboplatin

Study Arms

• Experimental: Trabectedin
  Trabectedin 1.3 mg/m2 d1 q 21 in 3 hours (central line)
  Intervention: Drug: Trabectedin
• Standard Treatment
  Pegylated Liposomal Doxorubicin 40 mg/mq q 28 or Topotecan 4 mg/ m2 dd 1,8,15 q 28 or Gemcitabine 1000 mg/mq dd 1, 8, 15 q 28 Weekly Paclitaxel 80 mg/ m2 dd 1, 8, 15 q 28 Carboplatin AUC 5-6 q 21 or 28
  Interventions:

  • Drug: Pegylated Liposomal Doxorubicin
  • Drug: Topotecan
  • Drug: Gemcitabine
  • Drug: Weekly Paclitaxel
  • Drug: Carboplatin

Publications *

• Salutari V, Ferrandina G, Vincenzi B et al. Efficacy and safety outcomes in heavily pretreated patients (pts) with relapsed ovarian cancer (roc ) after single agent trabectedin. ASCO 2013, submitted.
• Monk BJ, Herzog T, Kay S et al. A randomized Phase III study of trabectedin with pegylated liposomal doxorubicin (PLD) versus PLD in relapsed, recurrent ovarian cancer (OC). Ann. Oncol. 19(Suppl. 8), (2009)
• K. L. Tedesco, J. L. Blum, A. Goncalves, J. Lubinski, N. Ben-Baruch, C. R. Osborne, P. Lardelli, A et al. phase II trial of trabectedin (T) in patients (pts) with HER2-positive and BRCA1/2 germ-line-mutated metastatic breast cancer (MBC). J Clin Oncol 28:15s, 2010 (suppl; abstr 1038)
• Takebayashi Y, Pourquier P, Zimonjic DB, Nakayama K, Emmert S, Ueda T, Urasaki Y, Kanzaki A, Akiyama SI, Popescu N, Kraemer KH, Pommier Y. Antiproliferative activity of ecteinascidin 743 is dependent upon transcription-coupled nucleotide-excision repair. Nat Med. 2001 Aug;7(8):961-6. doi: 10.1038/91008. Erratum In: Nat Med 2001 Nov;7(11):1255.
• Damia G, Silvestri S, Carrassa L, Filiberti L, Faircloth GT, Liberi G, Foiani M, D'Incalci M. Unique pattern of ET-743 activity in different cellular systems with defined deficiencies in DNA-repair pathways. Int J Cancer. 2001 May 15;92(4):583-8. doi: 10.1002/ijc.1221.
• Schoffski P, Taron M, Jimeno J, Grosso F, Sanfilipio R, Casali PG, Le Cesne A, Jones RL, Blay JY, Poveda A, Maki RG, Nieto A, Tercero JC, Rosell R. Predictive impact of DNA repair functionality on clinical outcome of advanced sarcoma patients treated with trabectedin: a retrospective multicentric study. Eur J Cancer. 2011 May;47(7):1006-12. doi: 10.1016/j.ejca.2011.01.016. Epub 2011 Mar 4.
• Germano G, Frapolli R, Belgiovine C, Anselmo A, Pesce S, Liguori M, Erba E, Uboldi S, Zucchetti M, Pasqualini F, Nebuloni M, van Rooijen N, Mortarini R, Beltrame L, Marchini S, Fuso Nerini I, Sanfilippo R, Casali PG, Pilotti S, Galmarini CM, Anichini A, Mantovani A, D'Incalci M, Allavena P. Role of macrophage targeting in the antitumor activity of trabectedin. Cancer Cell. 2013 Feb 11;23(2):249-62. doi: 10.1016/j.ccr.2013.01.008.
• del Campo JM, Sessa C, Krasner CN, Vermorken JB, Colombo N, Kaye S, Gore M, Zintl P, Gomez J, Parekh T, Park YC, McMeekin S. Trabectedin as single agent in relapsed advanced ovarian cancer: results from a retrospective pooled analysis of three phase II trials. Med Oncol. 2013 Mar;30(1):435. doi: 10.1007/s12032-012-0435-1. Epub 2013 Feb 9.
• Erba E, Bergamaschi D, Bassano L, Damia G, Ronzoni S, Faircloth GT, D'Incalci M. Ecteinascidin-743 (ET-743), a natural marine compound, with a unique mechanism of action. Eur J Cancer. 2001 Jan;37(1):97-105. doi: 10.1016/s0959-8049(00)00357-9.
• Herrero AB, Martin-Castellanos C, Marco E, Gago F, Moreno S. Cross-talk between nucleotide excision and homologous recombination DNA repair pathways in the mechanism of action of antitumor trabectedin. Cancer Res. 2006 Aug 15;66(16):8155-62. doi: 10.1158/0008-5472.CAN-06-0179.
• Safra T, Borgato L, Nicoletto MO, Rolnitzky L, Pelles-Avraham S, Geva R, Donach ME, Curtin J, Novetsky A, Grenader T, Lai WC, Gabizon A, Boyd L, Muggia F. BRCA mutation status and determinant of outcome in women with recurrent epithelial ovarian cancer treated with pegylated liposomal doxorubicin. Mol Cancer Ther. 2011 Oct;10(10):2000-7. doi: 10.1158/1535-7163.MCT-11-0272. Epub 2011 Aug 11.
• Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, Verweij J, Van Glabbeke M, van Oosterom AT, Christian MC, Gwyther SG. New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst. 2000 Feb 2;92(3):205-16. doi: 10.1093/jnci/92.3.205.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: August 24, 2021): 242
• Original Estimated Enrollment (submitted: September 12, 2016): 244
• Actual Study Completion Date: December 20, 2018
• Actual Primary Completion Date: December 20, 2018 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

1. Female of age 18 years or older
2. Histologically or cytologically documented invasive epithelial ovarian cancer, primary peritoneal carcinoma, or fallopian tube cancer

3. Platinum resistant or sensitive patients with either:

   1. BRCA mutated patients
   2. BRCAness phenotype patients: patients who have received and responded (subsequent PFI>6 months) to at least 2 previous platinum based chemotherapy lines
   3. Platinum sensitive patients who are not able to receive or not willing to receive other platinum treatments
4. Measurable and evaluable disease per RECIST 1.1(Subjects with isolated rising CA-125 without radiologically visible disease are excluded)
5. ECOG performance status 0 or 1
6. No limits in the number of previous chemotherapy lines, previous treatment with parp inhibitors is allowed
7. Left Ventricular Ejection Fraction (LVEF) ≥ institutional lower limit normal
8. Life expectancy of at least 3 months

9. Adequate organ functions:

   1. Hematopoietic: Absolute neutrophil count ≥ 1,500/mm3; Platelet count ≥ 100,000/mm3; Hemoglobin ≥ 9 g/dl
   2. Hepatic: AST and ALT ≤ 1.5 times upper limit of normal (ULN)* ; Alkaline Phosphatase ≤ 2.5 times ULN* ; Bilirubin ≤ 1.5 times ULN. NOTE: * ≤ 3 times ULN if liver metastases are present
   3. Renal: Creatinine Clearance ≥ 45 ml/min or Serum Creatinine ≤1.5 x ULN
   4. Serum Albumin >2.5 g/dl
10. No other invasive malignancy within the past 3 years except non-melanoma skin cancer or in situ cervical cancer (patients with previous cancers may be enrolled providing that no recurrences have be reported in the last 3 years)
11. Written Informed Consent
12. Adequately recovered from the acute toxicity of any prior treatment
13. For agents in the standard arm, also refer to the local prescribing information with regards to warnings, precautions, and contraindications

Exclusion Criteria:

1. Prior exposure to trabectedin
2. Known hypersensitivity to any of the components of the trabectedin i.v. formulation or dexamethasone
3. Subjects with borderline ovarian cancer, ie. Subject with low malignant potential tumors are excluded
4. Less than 2 reported responses to platinum (i.e. subsequent recurrences at least 6 months after the first and the second platinum based treatment), unless BRCA mutation is documented.
5. Less than 4 weeks from last dose of therapy with any investigational agent, or chemotherapy
6. History of another neoplastic disease (except basal cell carcinoma or cervical carcinoma in situ adequately treated) unless in remission for 3 years or longer
7. Known clinically relevant CNS metastases, unless treated and asymptomatic

8. Other serious illnesses, such as:

   1. Congestive heart failure or angina pectoris; myocardial infarction within 1 year before enrolment; uncontrolled arterial hypertension or arrhythmias.
   2. Psychiatric disorder that prevents compliance with protocol.
   3. Active viral hepatitis; or chronic liver disease.
   4. Active infection.
   5. Any other unstable medical conditions.

Sex/Gender

• Sexes Eligible for Study: Female

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Italy

Administrative Information

• NCT Number: NCT02903004
• Other Study ID Numbers: 986
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Original Responsible Party: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Current Study Sponsor: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Original Study Sponsor: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano
• Collaborators: Not Provided

Investigators

• Principal Investigator: Domenica Lorusso, Prof.; Fondazione Policlinico Universitario A. Gemelli, IRCCS

• PRS Account: Fondazione Policlinico Universitario Agostino Gemelli IRCCS
• Verification Date: August 2021