Symptoms and General Pathology

All Conditions

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Gland and Hormone Related Diseases

Skin and Connective Tissue Diseases

Rare Diseases

Recurrence

Carcinoma

Adenocarcinoma

Ovarian Neoplasms

Carcinoma, Ovarian Epithelial

Cystadenocarcinoma, Serous

Brenner Tumor

Cystadenocarcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Disease Attributes

Neoplasms, Cystic, Mucinous, and Serous

Neoplasms, Fibrous Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Ovarian Diseases

Adnexal Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Genital Neoplasms, Female

Urogenital Neoplasms

Gonadal Disorders

Endocrine System Diseases

Ovarian Cancer

Ovarian Epithelial Cancer

Ovarian Low Malignant Potential Tumor

Adenocarcinoma of the Appendix

Brenner Tumor of Ovary

Patients receive selumetinib sulfate PO BID on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Laboratory Biomarker Analysis

Pharmacological Study

Selumetinib

Selumetinib Sulfate

John H Farley

This phase II trial studies the side effects and how well selumetinib sulfate works in treating patients with low-grade ovarian cancer that has come back (recurrent). Selumetinib sulfate may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

PRIMARY OBJECTIVES:

I. To examine the tumor response rate of patients on AZD6244 (selumetinib sulfate) (NSC #748727).

II. To examine the acute toxicity of AZD6244 (NSC #748727) during the first course of treatment using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.

III. To define the pharmacokinetic profile for AZD6244, 100 mg administered orally twice daily.

SECONDARY OBJECTIVES:

I. To examine the toxicity of AZD6244 (NSC #748727) using the 21 major categories of the CTCAE version 3.0.

II. To examine the dose and number of courses of AZD6244 (NSC #748727) given. III. To estimate the progression free survival, and overall survival of women receiving AZD6244 (NSC #748727).

TRANSLATIONAL RESEARCH OBJECTIVES:

I. To examine deoxyribonucleic acid (DNA) isolation with sequencing of braf, and ras mutation analysis and to explore their relationship with tumor response with AZD6244 (NSC #748727).

II. To examine protein levels of phosphorylated (p)-ERK/ERKERK) and explore their relationship with tumor response in patients treated with AZD6244 (NSC #748727).

OUTLINE:

Patients receive selumetinib sulfate orally (PO) twice a day (BID) on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Patients undergo blood sample collection periodically for correlative and pharmacokinetic studies and to analyze selumetinib sulfate peak concentrations and the corresponding peak time values. Previously collected archived tumor tissue samples are obtained to determine protein levels of p-ERK/ERKERK, DNA isolation and sequencing of BRAF and ras mutation analysis by immunohistochemistry (IHC).

After completion of study treatment, patients are followed every 3 months for 2 years, every 6 months for 3 years, and then once a year for 5 years.

Selumetinib Sulfate in Treating Woman With Recurrent Low-Grade Ovarian Cancer or Peritoneum Cancer

A Phase II Trial of AZD6244 (NSC# 748727) in Women With Recurrent Low-Grade Serous Carcinoma of the Ovary or Peritoneum

Complete and Partial Tumor Response by (Response Evaluation Criteria in Solid Tumors) RECIST 1.0

NRG Oncology

National Cancer Institute (NCI)

Includes all adverse events reported (grade 1-5) regardless of attribution.

AZD6244 (NSC #748727) 100 mg orally BID until disease progression or adverse effects prohibit further therapy (1 cycle =28 days)

AZD6244

20-29 years

30-39 years

40-49 years

50-59 years

60-69 years

70-79 years

80-89 years

Age, Customized

Sex: Female, Male

Study began with 100mg BID mix \& drink (MD) formulation. AstraZeneca (AZ) switched to hydrogen-sulfate capsule (HC). AZ deemed 100mg BID MD equivalent to 50mg BID HC. As of 12/31/2010, patients got 50mg BID HC; four patients were on treatment then.

Angela M. Kuras, Associate Director of Data Management

Tumor Response

Progression-free Survival

Eligible and Treated Patients. Two patients still on study and have received 68 and 79 cycles of treatment.

Number of Courses Received

Leukopenia

Thrombocytopenia

Neutropenia

Anemia

Allergy/Immunology

Auditory/Ear

Cardiac

Coagulation

Constitutional

Dermatologic

Gastrointestinal

Genitourinary/Renal

Hemorrhage

Infection

Lymphatics

Metabolic

Musculoskeletal

Neurosensory

Other Neurological

Ocular/Visual

Pain

Pulmonary

Adverse Events (Grade 3 or Higher) During First Cycle of Treatment

Eligible and Treated Patients with all pharmacokinetic time points available

Area Under the Curve (AUC) for AZD6244, 100 mg Administered Orally Twice Daily.

Eligible and Treated Patients with at least one post-dose pharmacokinetic time point available

Maximum Concentration (Cmax) for AZD6244, 100 mg Administered Orally Twice Daily.

Overall Survival

Overall Study

Antineoplastic Agents

All Drugs and Chemicals

Bone Density Conservation Agents

Anticoagulants

Anti-Infective Agents

Other Dietary Supplements

Paclitaxel

Albumin-Bound Paclitaxel

Tamoxifen

Doxorubicin

Liposomal doxorubicin

Letrozole

Topotecan

Citric Acid

Sodium Citrate

Trametinib

Dimethyl Sulfoxide

Tubulin Modulators

Antimitotic Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Aromatase Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormones

Hormone Antagonists

Topoisomerase I Inhibitors

Antineoplastic Agents, Hormonal

Selective Estrogen Receptor Modulators

Estrogen Receptor Modulators

Protein Kinase Inhibitors

Protective Agents

Antioxidants

Citrate

Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.

Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Pegylated Liposomal Doxorubicin Hydrochloride

Quality-of-Life Assessment

Questionnaire Administration

Tamoxifen Citrate

Trametinib Dimethyl Sulfoxide

David M Gershenson

This phase II/III trial studies how well trametinib works and compares it to standard treatment with either letrozole, tamoxifen, paclitaxel, pegylated liposomal doxorubicin, or topotecan in treating patients with low-grade ovarian cancer or peritoneal cavity cancer that has come back (recurrent), become worse (progressive), or spread to other parts of the body. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether trametinib is more effective than standard therapy in treating patients with ovarian or peritoneal cavity cancer.

PRIMARY OBJECTIVE:

I. To estimate the progression-free survival (PFS) hazard ratio of trametinib compared to that of "commercially available therapies" consisting of one of five commercially available agents in women with recurrent low-grade serous carcinoma of the ovary or peritoneum previously treated with platinum-based chemotherapy.

SECONDARY OBJECTIVES:

I. To determine the nature, frequency and maximum degree of toxicity as assessed by Common Terminology Criteria for Adverse Events (CTCAE) version (v) 4 for each treatment arm.

II. To determine the quality of life, as assessed by the Functional Assessment of Cancer Therapy-Ovarian (FACT-O).

IIa. To compare trametinib to the control arm with regard to patients' self-reported acute (up to post-cycle 6) quality of life as measured by the FACT-O-Trial Outcome Index (TOI).

IIb. To compare trametinib to the control arm with regard to patients' self-reported acute (up to post-cycle 6) neurotoxicity as measured by the FACT-Gynecologic Oncology Group (GOG)-Neurotoxicity (NTX).

III. To estimate the objective response rate (RR) of patients in each treatment arm.

IV. To test whether high expression of pERK, as quantified by immunohistochemistry (IHC), is associated with better prognosis (RR or PFS) among patients receiving the randomized treatment.

V. To test whether genetic changes associated with MAPK pathway activation (KRAS, NRAS, HRAS, BRAF, MEK, ERBB2 or NF1) are associated with improved prognosis (RR or PFS) among patients receiving the randomized treatment.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive clinician's choice of either letrozole orally (PO) once daily (QD) on days 1-28, tamoxifen citrate PO twice daily (BID) on days 1-28, paclitaxel intravenously (IV) over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride (PLD) IV over 1 hour on day 1, or topotecan IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.

ARM B: Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years, every 6 months for 3 years, and then annually for 5 years.

Trametinib in Treating Patients With Recurrent or Progressive Low-Grade Ovarian Cancer or Peritoneal Cavity Cancer

A Randomized Phase II/III Study to Assess the Efficacy of Trametinib (GSK 1120212) in Patients With Recurrent or Progressive Low-Grade Serous Ovarian Cancer or Peritoneal Cancer

Progression free survival (PFS) was defined as the number of months between study enrollment and documentation of disease progression (RECIST 1.1) or death from any cause. Patients still alive and disease free at the last followup were censored on the date of last CT Scan.Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the PFS endpoint definition.

Number of treated patients with Adverse Events (grade 3 or higher) observed while receiving randomized therapy. Excludes AEs observed among control patients treated with trametinib after crossover.Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the AE endpoint definition.

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. Patients with disease progression on the Control arm were allowed to cross over to the trametinib arm. Per the protocol, the intent-to-treat OS analysis was not adjusted for crossover.

The Response Rates were estimated as the binomial proportion of patients with Best Overall Response of Complete or Partial response according to RECIST 1.1 criteria.

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-O TOI is a scale for assessing general QOL of ovarian cancer patients. It consists of three subscales: Physical Well Being (7 items), Functional Well Being (7 items), and Ovarian Cancer subscale (11 items). . The FACT-O TOI score is calculated as the sum of the subscale scores if more than 80% of the FACT-O TOI items provide valid answers and all of the component subscales have valid scores. The FACT-O TOI score ranges 0-100 with a large score suggesting better QOL. Participants were analyzed based on their group of assignment. Patients on Arm A who progressed were permitted to receive Arm B treatment. Study time for Arm A patients who crossed over was not included in the quality of life endpoint definition

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 FACT/GOG-Ntx subscale contains 4 items. Each item was scored using a 5-point scale (0=not at all; 1=a little bit; 2=somewhat; 3=quite a bit; 4=very much). According to the FACIT measurement system, the Ntx score was the summation of the individual item scores if more than 50% of subscale items were answered. When unanswered items existed, a subscale score was prorated by multiplying the mean of the answered item scores by the number of items in the scale. The Ntx score ranges 0-16 with a large score suggesting less peripheral neuropathy symptoms

Progression free survival (PFS) was defined as the number of months between study enrollment and documentation of disease progression (RECIST 1.1) or death from any cause. Patients still alive and disease free at the last followup were censored on the date of last CT Scan. RECIST v1.1 defines progression as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5 mm. The appearance of one or more new lesions is also considered progression.

Will be quantified using the H-score derived from the immunohistochemistry analysis of patient tumor tissue and is expected to present as a continuous measure. will consider the prognostic and predictive abilities of pERK relative to objective response rate (ORR) or PFS. Analysis of the dichotomous markers will be supported by Kaplan Meier plots, and forest plots of the odds-ratio and hazard ratio estimates. Duration of response will be depicted using swimmer plots, with median duration estimated using Kaplan Meier methods. The multivariable models will include covariate adjustment for geographic region, performance status and number of prior regimens, presented using effect coding. The adjusted hazard- and odds- ratio estimates from the multivariable models will be supported by nominal p-values and 2-sided, 95% confidence intervals. Confidence intervals will be interpreted as the plausible range of values for the true (unobserved) ratio that is supported by the data.

Investigators choice of Letrozole 2.5 mg po qd continuously, tamoxifen 20mg po bid continuously, paclitaxel 80mg/m2 IV over 1 hr on day 1q 7d, 3 wks on, 1 wk off, Pegylated Liposomal Doxorubicin 40 or 50mg/m2 IV over 1 hr on day 1 q. 28d, Topotecan 4.0mg/m2 over 30 min on day 1,8 and 15 of a 28 day cycle. For each arm, 1 cycle - 28 days

Arm A - Control Arm

Trametinib 2 mg po daily continuous treatment, For each arm, 1 cycle = 28 days

Arm B - Experimental Arm

Patients randomized to the control arm who crossed over to the experimental arm after disease progression.

Crossover From Control to Experimental Arm

Total

Age, Continuous

>= 70 years

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

United Kingdom

Region of Enrollment

1 Prior Treatment Regimens

2 Prior Treatment Regimens

3 or More Prior Treatment Regimens

Number of Prior Treatment Regimens

The pERK expression analysis is still under development, and will not be available for approximately 2 - 3 years.

Linda Gedeon for Austin Miller, PhD

Progression-free Survival (PFS)

Abdominal pain

Diarrhea

Fatigue

Hypertension

Nausea

Neutrophil count decreased

Rash maculo-papular

Small Intestinal Obstruction

Vomiting

Incidence of Adverse Events (AEs)

Objective Tumor Response Rate (Complete Response and Partial Response)

Baseline

12 Weeks

24 Weeks

36 Weeks

52 Weeks

Patients receive clinician's choice of either letrozole PO QD on days 1-28, tamoxifen citrate PO BID on days 1-28, paclitaxel IV over 1 hour on days 1, 8, and 15, pegylated liposomal doxorubicin hydrochloride IV over 1 hour on day 1, or topotecan hydrochloride IV over 30 minutes on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients developing progressive disease may cross over to Arm B.

Letrozole: Given PO

Paclitaxel: Given IV

Pegylated Liposomal Doxorubicin Hydrochloride: Given IV

Quality-of-Life Assessment: Ancillary studies

Tamoxifen: Given PO

Tamoxifen Citrate: Given PO

Topotecan: Given IV

Topotecan Hydrochloride: Given IV

Arm A (Letrozole, Tamoxifen, Paclitaxel, PLD, Topotecan)

Patients receive trametinib PO QD on days 1-28. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Quality-of-Life Assessment: Ancillary studies

Trametinib: Given PO

Trametinib Dimethyl Sulfoxide: Given PO

Arm B (Trametinib)

Patients who provided baseline and ≥ 1 follow-up assessment

Patients Reported Acute Quality of Life

Patients that provided baseline and ≥ 1 follow-up assessment

Patient Reported Acute Peripheral Neuropathy Symptoms

Prognostic effect of the mutation status among patients in the SOC arm.

Patients with sufficient tissue for analysis

Progression Free Survival

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Selumetinib Sulfate in Treating Woman With Recurrent Low-Grade Ovarian Cancer or Peritoneum Cancer	NCT00551070	Borderline Ovar... Low Grade Ovari... Micropapillary ... Primary Periton... Primary Periton... Recurrent Borde...	Laboratory Biom... Pharmacological... Selumetinib Selumetinib Sul...	19 Years -	National Cancer Institute (NCI)
Trametinib in Treating Patients With Recurrent or Progressive Low-Grade Ovarian Cancer or Peritoneal Cavity Cancer	NCT02101788	Borderline Ovar... Micropapillary ... Ovarian Serous ... Primary Periton... Recurrent Ovari... Recurrent Prima...	Letrozole Paclitaxel Pegylated Lipos... Quality-of-Life... Questionnaire A... Tamoxifen Citra... Topotecan Trametinib Dime...	18 Years -	National Cancer Institute (NCI)

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