Paclitaxel, Polyglutamate Paclitaxel, or Observation in Treating Patients With Stage III or Stage IV Ovarian Epithelial, Peritoneal Cancer, or Fallopian Tube Cancer

PRIMARY OBJECTIVES:

I. To determine whether CT-2103 (polyglutamate paclitaxel) or paclitaxel, administered to women with advanced ovarian, primary peritoneal or fallopian tube cancer who have attained a clinically-defined complete response to primary platinum/taxane-based chemotherapy ("consolidation/maintenance therapy") will reduce the death rate, compared to re-treatment at the time of documented disease progression.

II. To determine if, in this clinical setting, CT-2103 produces a more favorable toxicity profile (with a particular focus on peripheral neuropathy as measured by the Gynecologic Oncology Group \[GOG\] NTX4) and superior quality-of-life (as measured by the Functional Assessment of Cancer Therapy-Ovarian \[FACT-O\]), compared to paclitaxel.

SECONDARY OBJECTIVES:

I. To explore the relationship between expression of several of the angiogenic markers and overall survival or progression-free survival in patients randomized to CT-2103, paclitaxel, or no treatment.

II. To assess the association among the various tissue and serum markers of angiogenesis, and compare the ability of different combinations of these markers to predict patient outcome including overall survival and progression-free survival in patients randomized to CT-2103, paclitaxel, or no treatment.

III. To bank deoxyribonucleic acid (DNA) from whole blood for research and evaluate the association between single nucleotide polymorphisms (SNPs) and measures of clinical outcome including overall survival, progression-free survival and adverse events.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM I: Patients receive polyglutamate paclitaxel intravenously (IV) over 10-20 minutes on day 1.

ARM II: Patients receive paclitaxel IV over 3 hours on day 1.

ARM III: Patients receive no further anticancer treatment until evidence of disease progression.

In arms I and II, treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed every 3 months for 2 years and then every 6 months for 10 years.

• Clinical Observation (Other), also known as observation: Undergo observation
• Laboratory Biomarker Analysis (Other): Correlative studies
• Paclitaxel (Drug), also known as Anzatax, Asotax, Bristaxol, Praxel, Taxol, Taxol Konzentrat: Given IV
• Paclitaxel Poliglumex (Drug), also known as CT-2103, CT2103, Paclitaxel Polyglutamate, Paclitaxel-Polyglutamate Polymer, PG-TXL, Poly-L-Glutamic acid-Paclitaxel Conjugate, Polyglutamic Acid Paclitaxel, Xyotax: Given IV
• Quality-of-Life Assessment (Procedure), also known as Quality of Life Assessment: Ancillary studies

Primary outcomes

• Overall Survival [All patients were followed (with physical exams and histories) every three months for the first two years, then every six months for the next three years and then annually for the next five years.]: Overall survival (OS) was defined as the number of months between study enrollment and death from any cause. Patients still alive at the last follow-up were censored on the date of last contact.

Secondary outcomes

• Progression-free Survival [Progression was assessed every 8 weeks for the first 15 months, then every 3 months, up to 14.2 years.]: Progression free survival (PFS) was defined as the number of months between study enrollment and the date of first clinical, biochemical, or radiological evidence of progression or death due to any cause. Patients who were alive without progression at the time of analysis were censored on the date of the last tumor assessment.
• Frequency and Severity of Adverse Effects Assessed by CTCAE v3.0 [Measured within 6 months of enrollment; through all cycles of chemotherapy and up to 30 days after the last cycle of chemotherapy. Up to 10 cycles of chemotherapy were allowed. Cycles were to be repeated every 3 weeks.]: Number of treated patients with Adverse Events (grade 3 or higher) observed while receiving randomized therapy among adverse event terms with at least 4 patients reporting.
• Patient-Reported Quality of Life (QOL) [1. Prior to treatment 2. Prior to cycle 3 3. Prior to cycle 5 4. Prior to cycle 7 5. Prior to cycle 12 6. 12 months post treatment]: Patient reported quality of life was measured with the Treatment Outcome Index (TOI) of the Functional Assessment of Cancer Therapy for ovarian cancer (FACT-O TOI). The FACT-En TOI is a scale for assessing general QOL of ovarian cancer patients. The FACT-O TOI score ranges 0-100 with a large score suggesting better QOL.
• Patient-Reported Peripheral Neuropathy Symptoms [1. Prior to treatment 2. Prior to cycle 3 3. Prior to cycle 5 4. Prior to cycle 7 5. Prior to cycle 12 6. 12 months post treatment]: Patient reported peripheral neuropathy symptoms was measured with the Functional Assessment of Cancer Therapy/ Gynecologic Oncology Group - neurotoxicity subscale (short version) (FACT/GOG-Ntx subscale). The Ntx score ranges 0-16 with a large score suggesting less peripheral neuropathy symptoms.

Sex: Female

Inclusion Criteria:

* Patients with a histologic diagnosis of primary peritoneal carcinoma, or stage III or IV epithelial ovarian or fallopian tube carcinoma, with either optimal (=< 1 cm residual disease) or suboptimal residual disease following initial surgery; all patients must have had appropriate surgery for ovarian, primary peritoneal or fallopian tube carcinoma with appropriate tissue available for histologic evaluation to confirm diagnosis and stage
* Patients with the following histologic epithelial cell types are eligible:

  * Serous adenocarcinoma
  * Endometrioid adenocarcinoma
  * Mucinous adenocarcinoma
  * Undifferentiated carcinoma
  * Clear cell adenocarcinoma
  * Mixed epithelial carcinoma
  * Transitional cell carcinoma
  * Malignant Brenner tumor
  * Adenocarcinoma not otherwise specified (NOS)
* Patients must have completed treatment within the past 12 weeks with at least 5 cycles and not more than 8 cycles of a platinum (IV or intraperitoneal \[IP\]) and paclitaxel or docetaxel-based combination chemotherapy and have no symptoms suggestive of persistent cancer, normal (no evidence of cancer) computed tomography (CT) scan of the abdomen/pelvis and normal cancer antigen 125 (CA-125) following this therapy

  * Patients treated with neo-adjuvant platinum-taxane chemotherapy for a presumptive diagnosis of stage III or IV epithelial ovarian, primary peritoneal or, fallopian tube (by paracentesis, percutaneous biopsy or open biopsy) are eligible provided that they have undergone interval abdominal surgery after at least one but no more than six cycles of standard chemotherapy; such surgery must meet the same criteria as for those undergoing up front surgery, including tissue diagnosis for confirmation of primary tumor site and stage III or IV disease; also, patients must have received at least two cycles after interval abdominal surgery
* Absolute neutrophil count >= 1,500/ul, equivalent to Common Toxicity Criteria (CTCAE version \[v\]3.0) grade 1
* Platelet count >= 100,000/ul
* Creatinine =< 1.5 times institutional upper limit of normal (ULN), CTCAE v3.0 grade 1
* Bilirubin =< 1.5 times ULN, (CTCAE v3.0 grade 1)
* Serum glutamic oxaloacetic transaminase (SGOT) =< 2.5 times ULN (CTCAE v3.0 grade 1)
* Alkaline phosphatase =< 2.5 times ULN (CTCAE v3.0 grade 1)
* Neuropathy (sensory and motor) less than or equal to CTCAE v3.0 grade 1
* Gynecologic Oncology Group (GOG) performance status of 0, 1, or 2
* Patients must have signed an approved informed consent and Health Insurance Portability and Accountability Act (HIPAA) authorization
* Patients must complete pre-entry assessments

Exclusion Criteria:

* Patients with a current diagnosis of epithelial ovarian or fallopian tube tumor of low malignant potential (LMP) (Borderline carcinomas) are not eligible; patients with a prior diagnosis of a low malignant potential tumor that was surgically resected and who subsequently develop invasive adenocarcinoma are eligible, provided that they have not received prior chemotherapy for their ovarian LMP tumor
* Germ cell tumors, sex cord-stromal tumors, carcinosarcomas, mixed mullerian tumors or carcinosarcomas, metastatic carcinomas from other sites to the ovary and low malignant potential tumors including so called micropapillary serous carcinomas are not eligible
* Patients who have received prior radiotherapy to any portion of the abdominal cavity or pelvis are excluded; prior radiation for localized cancer of the breast, head and neck, or skin is permitted, provided that it was completed more than 3 years prior to registration, and the patient remains free of recurrent or metastatic disease
* Patients who have received investigational therapies, and/or biological therapies (i.e. Bevacizumab or Erlotinib) for their epithelial ovarian, primary peritoneal or fallopian tube cancers or for any other abdominal or pelvic tumor, are not excluded; however, biologics cannot be continued concurrent with the GOG-012 maintenance treatment (or observation); patients who have received prior chemotherapy for any other abdominal or pelvic tumor (except as noted above) are excluded; patients may have received prior adjuvant chemotherapy for localized breast cancer, provided that it was completed more than 3 years prior to registration, and that the patient remains free of recurrent or metastatic disease
* Patients with synchronous primary endometrial cancer, or a past history of primary endometrial cancer, are excluded, unless all of the following conditions are met:

  * Stage not greater than I-B
  * Less than 3 mm invasion without vascular or lymphatic invasion
  * No poorly differentiated subtypes, including papillary serous, clear cell, or other Federation of Gynecology and Obstetrics (FIGO) Grade 3 lesions
* With the exception of non-melanoma skin cancer and other specific malignancies as noted above, patients with other invasive malignancies who had (or have) any evidence of the other cancer present within the last 5 years or whose previous cancer treatment contraindicates this protocol therapy are excluded
* Patients with acute hepatitis, or known chronic hepatitis
* Patients with an active infection that requires antibiotics
* Patients with ongoing gastrointestinal bleeding requiring blood product support
* Patients whose circumstances at the time of entry onto the protocol would not permit completion of study or required follow up
* Patients with unstable angina or those who have had a myocardial infarction within the past six months; patients with evidence of abnormal cardiac conduction (e.g. bundle branch block, heart block) are eligible if their disease has been stable for the past six months
* Patients are excluded who have had prior therapy with CT-2103
* Patients with active bleeding or an unexplained prothrombin time (PT) or partial thromboplastin time (PTT) > institutional upper limit normal (ULN)
* Patients who are pregnant or nursing are excluded; patients who may become pregnant must practice an effective method of birth control

Participant flow

Outcome results

• Overall Survival (Primary), Median, Months: Arm I (Paclitaxel Poliglumex) 60.0 (51.7 to 68.6); Arm II (Paclitaxel) 56.8 (47.3 to 65.9); Arm III (Observation) 58.3 (51.9 to 72.5)
• Progression-free Survival (Secondary), Median, Months: Arm I (Paclitaxel Poliglumex) 16.3 (14.4 to 18.9); Arm II (Paclitaxel) 18.9 (17.0 to 21.8); Arm III (Observation) 13.4 (11.2 to 15.7)
• Frequency and Severity of Adverse Effects Assessed by CTCAE v3.0 (Secondary), Number, participants: Arm I (Paclitaxel Poliglumex) 4; Arm II (Paclitaxel) 0; Arm III (Observation) 0
• Patient-Reported Quality of Life (QOL) (Secondary), Mean, score on a scale: Arm I (Paclitaxel Poliglumex) 78.2 +/- 0.6; Arm II (Paclitaxel) 77.3 +/- 0.7; Arm III (Observation) 77.4 +/- 0.7
• Patient-Reported Peripheral Neuropathy Symptoms (Secondary), Mean, score on a scale: Arm I (Paclitaxel Poliglumex) 11.4 +/- 0.2; Arm II (Paclitaxel) 11.7 +/- 0.2; Arm III (Observation) 11.8 +/- 0.2

Adverse events

Time frame: All patients were followed (with physical exams and histories) every three months for the first two years, then every six months for the next three years and then annually for the next 5 years.

Serious adverse events by term

2 more terms not shown.

Other adverse events by term

272 more terms not shown.

215 more sites not listed.

• Results publication: Copeland LJ, Brady MF, Burger RA, Rodgers WH, Huang HQ, Cella D, O'Malley DM, Street DG, Tewari KS, Bender DP, Morris RT, Lowery WJ, Miller DS, Dewdney SB, Spirtos NM, Lele SB, Guntupalli S, Ueland FR, Glaser GE, Mannel RS, DiSaia PJ. Phase III Randomized Trial of Maintenance Taxanes Versus Surveillance in Women With Advanced Ovarian/Tubal/Peritoneal Cancer: A Gynecologic Oncology Group 0212:NRG Oncology Study. J Clin Oncol. 2022 Dec 10;40(35):4119-4128. doi: 10.1200/JCO.22.00146. Epub 2022 Jun 27. PMID 35759733

• Study Protocol and Statistical Analysis Plan (PDF, 2014-12-17)

• Larry J Copeland, Principal investigator, NRG Oncology

NIH grants: U10CA180868, U10CA027469