Auranofin and Sirolimus in Treating Participants With Ovarian Cancer

• Sponsor: Mayo Clinic (Other)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT03456700
• Collaborator: National Cancer Institute (NCI) (NIH)
• Enrollment: 22
• Location: 1
• Arm: 1
• Anticipated Duration (Months): 59.5
• Patients Per Site Per Month: 0.4

Study Details

Study Description

Brief Summary

This phase II trial studies how well auranofin and sirolimus work in treating participants with ovarian cancer. Immunosuppressive therapy, such as auranofin and sirolimus, is used to decrease the body?s immune response and may increase blood cell count.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Serous Tumor; Recurrent Ovarian Carcinoma	Drug: Auranofin; Other: Laboratory Biomarker Analysis; Drug: Sirolimus	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To estimate the overall tumor response rate (ORR, that is, complete response [CR] + partial response [PR]) of the combination of auranofin and sirolimus in the setting of metastatic serous ovarian cancer across all patients.

SECONDARY OBJECTIVES:

1. To estimate the overall tumor response rate (ORR, that is, complete response [CR] + partial response [PR]) of the combination of auranofin and sirolimus in the setting of metastatic serous ovarian cancer within patients that have overexpression of PKCiota.

2. To estimate progression-free survival, overall survival, and adverse events from the combination of auranofin and sirolimus.

CORRELATIVE OBJECTIVES:

1. To explore whether PKCiota-relevant biomarkers in serous ovarian cancer tumors are associated with treatment response patterns, such as ORR, progression free survival, and overall survival.

OUTLINE:

Participants receive auranofin orally (PO) once daily (QD) and sirolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.

After completion of study treatment, participants are followed up every 6 months for 3 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 22 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Trial to Evaluate the Efficacy of Auranofin and Sirolimus in Serous Ovarian Cancer Patients With Recurrent Disease
• Actual Study Start Date: Mar 30, 2018
• Actual Primary Completion Date: Jul 31, 2019
• Anticipated Study Completion Date: Mar 15, 2023

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment (auranofin, sirolimus) Participants receive auranofin PO QD and sirolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.	Drug: Auranofin; Given PO; Other Names: Ridaura ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Sirolimus; Given PO; Other Names: AY 22989 RAPA Rapamune Rapamycin SILA 9268A WY-090217

Outcome Measures

Primary Outcome Measures

1. Number of Participants With a Confirmed Tumor Response (Partial Response [PR] or Complete Response [CR] at Least 4 Weeks Apart) [1 year 4 months]

   The outcome measure is the number of participants with a confirmed tumor response (partial response [PR] or complete response [CR] at least 4 weeks apart). PR and CR are defined using RECIST 1.1 criteria. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target and non-target lesions and normalisation of tumour marker level. Any pathological lymph nodes must have reduction in short axis to <10 mm.

Secondary Outcome Measures

1. Number of Participants With a Confirmed Tumor Response (PR or CR at Least 4 Weeks Apart) in the Subset of Participants That Have Over-expression of Protein Kinase C (PKC) Iota [1 year 4 months]

   The outcome measure is the number of participants with a confirmed tumor response (partial response [PR] or complete response [CR] at least 4 weeks apart) in the subset of participants that have overexpression of PKC iota. PR and CR are defined using RECIST 1.1 criteria. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target and non-target lesions and normalisation of tumour marker level. Any pathological lymph nodes must have reduction in short axis to <10 mm.

2. Progression-free Survival (PFS) [1 year 4 months]

   Progression-free survival (PFS) is defined as the time from registration to the first of either disease progression or death from any cause. Patients who receive the study drug, but then never return for an evaluation will be censored on their last follow-up date. PFS will be estimated using the method of Kaplan-Meier. Progression is defined using RECIST 1.1 criteria; Progression: At least a 20% increase in the sum of 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. (Note: the appearance of one or more new lesions is also considered progression), Unequivocal progression (see comments below) of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression), or appearance of new malignant lesions.

3. Overall Survival (OS) [1 year 4 months]

   Overall survival (OS) is defined as the time from registration to death from any cause. OS will be estimated using the method of Kaplan-Meier.

4. Number of Participants Experiencing at Least One Grade 3 or Worse Adverse Event (AE) [1 year 4 months]

   The outcome measure is the number of participants experiencing at least one grade 3 or worse adverse event (AE).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Eastern Cooperative Oncology Group (ECOG) performance score of 0 or 1

• Ovarian, Fallopian Tube or Primary Peritoneal cancer of serous histology

• Incurable cancer

• Willingness to provide paraffin-embedded tissue blocks of ovarian cancer

• Measurable disease

• Obtained =< 14 days prior to registration: Absolute neutrophil count (ANC) >= 1500 uL

• Obtained =< 14 days prior to registration: Platelet (PLT) >= 100,000 uL

• Obtained =< 14 days prior to registration: Hemoglobin (Hgb) >= 9 g/dL

• Obtained =< 14 days prior to registration: Total bilirubin =< 1.5 x upper limit of normal (ULN) or direct bilirubin =< ULN

• Obtained =< 14 days prior to registration: Serum glutamic-oxaloacetic transaminase (SGOT) (aspartate aminotransferase [AST]) and serum glutamate pyruvate transaminase (SGPT) (alanine aminotransferase [ALT]) =< 3 x ULN or SGOT (AST) and SGPT (ALT) =< 5 x ULN is acceptable if liver has tumor involvement

• Obtained =< 14 days prior to registration: Creatinine =< 1.5 x ULN

• Obtained =< 14 days prior to registration: Fasting serum glucose =< 1.5 x ULN

• Obtained =< 14 days prior to registration: Total cholesterol =< 1.5 x ULN

• Obtained =< 14 days prior to registration: Triglycerides =< 1.5 x ULN

• Life expectancy >= 12 weeks

Exclusion Criteria:

• Platinum-sensitive disease (exceptions allowed: patient has had a hypersensitivity reaction to platinum or the treating oncologist thinks that further platinum therapy is not in the patient?s best interest)

• Morbidities or concurrent major illness (for example, bowel obstruction or a second active malignancy) that, in the opinion of the treating healthcare provider, would make participation in the trial problematic

• Leptomeningeal disease or uncontrolled brain metastasis

• Failure to recover from acute, reversible effects of prior therapy regardless of interval since last treatment

• NOTE: Patients can have peripheral (sensory) neuropathy

• History of hypertriglyceridemia or hypercholesterolemia and currently on medication(s)

• Use of St. John?s wort =< 7 days prior to registration

• Unable to discontinue use of a strong CYP3A4 inhibitor

Contacts and Locations

Locations

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

Sponsors and Collaborators

• Mayo Clinic
• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Aminah Jatoi, Mayo Clinic

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Aug 3, 2018

More Information

Publications

None provided.

• Responsible Party: Mayo Clinic
• ClinicalTrials.gov Identifier: NCT03456700
• Other Study ID Numbers: MC1761; NCI-2018-00321; MC1761; P30CA015083
• First Posted: Mar 7, 2018
• Last Update Posted: Mar 24, 2022
• Last Verified: Mar 1, 2022

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Sirolimus; Auranofin

Study Results

Participant Flow

Arm/Group Title	Treatment (Auranofin, Sirolimus)
Arm/Group Description	Participants receive 6 mg auranofin PO QD and 5 mg sirolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Period Title: Overall Study
STARTED	22
COMPLETED	21
NOT COMPLETED	1

Baseline Characteristics

Arm/Group Title	Treatment (Auranofin, Sirolimus)
Arm/Group Description	Participants receive 6 mg auranofin PO QD and 5 mg sirolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Overall Participants	21
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61
Sex: Female, Male (Count of Participants)
Female	21 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	0 0%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	20 95.2%
More than one race	0 0%
Unknown or Not Reported	1 4.8%
Received prior chemotherapy for this cancer (Count of Participants)
Count of Participants [Participants]	20 95.2%
Tumor Over-expression of Protein Kinase C (PKC) iota (Count of Participants)
Count of Participants [Participants]	21 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With a Confirmed Tumor Response (Partial Response [PR] or Complete Response [CR] at Least 4 Weeks Apart)
Description	The outcome measure is the number of participants with a confirmed tumor response (partial response [PR] or complete response [CR] at least 4 weeks apart). PR and CR are defined using RECIST 1.1 criteria. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target and non-target lesions and normalisation of tumour marker level. Any pathological lymph nodes must have reduction in short axis to <10 mm.
Time Frame	1 year 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Auranofin, Sirolimus)
Arm/Group Description	Participants receive 6 mg auranofin PO QD and 5 mg sirolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Measure Participants	21
Count of Participants [Participants]	0 0%

2. Secondary Outcome

Title	Number of Participants With a Confirmed Tumor Response (PR or CR at Least 4 Weeks Apart) in the Subset of Participants That Have Over-expression of Protein Kinase C (PKC) Iota
Description	The outcome measure is the number of participants with a confirmed tumor response (partial response [PR] or complete response [CR] at least 4 weeks apart) in the subset of participants that have overexpression of PKC iota. PR and CR are defined using RECIST 1.1 criteria. PR: At least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum diameters. CR: Disappearance of all target and non-target lesions and normalisation of tumour marker level. Any pathological lymph nodes must have reduction in short axis to <10 mm.
Time Frame	1 year 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Auranofin, Sirolimus)
Arm/Group Description	Participants receive 6 mg auranofin PO QD and 5 mg sirolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Measure Participants	21
Count of Participants [Participants]	0 0%

3. Secondary Outcome

Title	Progression-free Survival (PFS)
Description	Progression-free survival (PFS) is defined as the time from registration to the first of either disease progression or death from any cause. Patients who receive the study drug, but then never return for an evaluation will be censored on their last follow-up date. PFS will be estimated using the method of Kaplan-Meier. Progression is defined using RECIST 1.1 criteria; Progression: At least a 20% increase in the sum of 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. (Note: the appearance of one or more new lesions is also considered progression), Unequivocal progression (see comments below) of existing non-target lesions. (Note: the appearance of one or more new lesions is also considered progression), or appearance of new malignant lesions.
Time Frame	1 year 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Auranofin, Sirolimus)
Arm/Group Description	Participants receive 6 mg auranofin PO QD and 5 mg sirolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Measure Participants	21
Median (95% Confidence Interval) [months]	2.1

4. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival (OS) is defined as the time from registration to death from any cause. OS will be estimated using the method of Kaplan-Meier.
Time Frame	1 year 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Auranofin, Sirolimus)
Arm/Group Description	Participants receive 6 mg auranofin PO QD and 5 mg sirolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Measure Participants	21
Median (95% Confidence Interval) [months]	4.4

5. Secondary Outcome

Title	Number of Participants Experiencing at Least One Grade 3 or Worse Adverse Event (AE)
Description	The outcome measure is the number of participants experiencing at least one grade 3 or worse adverse event (AE).
Time Frame	1 year 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Treatment (Auranofin, Sirolimus)
Arm/Group Description	Participants receive 6 mg auranofin PO QD and 5 mg sirolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
Measure Participants	21
Count of Participants [Participants]	13 61.9%

Adverse Events

Time Frame	Up to 2 years
Adverse Event Reporting Description	Participants evaluable for adverse events are summarized below (i.e. participants who did not withdraw consent).
Arm/Group Title	Treatment (Auranofin, Sirolimus)
Arm/Group Description	Participants receive 6 mg auranofin PO QD and 5 mg sirolimus PO QD on days 1-28. Courses repeat every 28 days in the absence of disease progression or unaccepted toxicity.
All Cause Mortality
	Treatment (Auranofin, Sirolimus)
	Affected / at Risk (%)	# Events
Total	19/21 (90.5%)
Serious Adverse Events
	Treatment (Auranofin, Sirolimus)
	Affected / at Risk (%)	# Events
Total	9/21 (42.9%)
Gastrointestinal disorders
Abdominal pain	1/21 (4.8%)	1
Mucositis oral	1/21 (4.8%)	1
Nausea	1/21 (4.8%)	1
Small intestinal obstruction	3/21 (14.3%)	3
Vomiting	2/21 (9.5%)	3
General disorders
Fatigue	1/21 (4.8%)	1
Fever	1/21 (4.8%)	1
Infections and infestations
Sepsis	2/21 (9.5%)	2
Metabolism and nutrition disorders
Hypokalemia	1/21 (4.8%)	1
Musculoskeletal and connective tissue disorders
Flank pain	1/21 (4.8%)	1
Renal and urinary disorders
Urinary tract obstruction	1/21 (4.8%)	1
Respiratory, thoracic and mediastinal disorders
Resp, thoracic, mediastinal - Oth spec	1/21 (4.8%)	1
Other (Not Including Serious) Adverse Events
	Treatment (Auranofin, Sirolimus)
	Affected / at Risk (%)	# Events
Total	20/21 (95.2%)
Blood and lymphatic system disorders
Anemia	16/21 (76.2%)	26
Gastrointestinal disorders
Abdominal pain	1/21 (4.8%)	1
Diarrhea	17/21 (81%)	32
Mucositis oral	12/21 (57.1%)	20
Nausea	11/21 (52.4%)	17
Vomiting	9/21 (42.9%)	12
General disorders
Edema limbs	3/21 (14.3%)	5
Fatigue	19/21 (90.5%)	40
Investigations
Alkaline phosphatase increased	2/21 (9.5%)	3
Cholesterol high	1/21 (4.8%)	1
Creatinine increased	3/21 (14.3%)	3
Lymphocyte count decreased	7/21 (33.3%)	12
Neutrophil count decreased	2/21 (9.5%)	2
Platelet count decreased	6/21 (28.6%)	12
White blood cell decreased	5/21 (23.8%)	5
Metabolism and nutrition disorders
Anorexia	6/21 (28.6%)	6
Hyperglycemia	1/21 (4.8%)	1
Hypertriglyceridemia	2/21 (9.5%)	2
Musculoskeletal and connective tissue disorders
Arthralgia	9/21 (42.9%)	15
Back pain	1/21 (4.8%)	1
Flank pain	1/21 (4.8%)	1
Myalgia	7/21 (33.3%)	12
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/21 (4.8%)	1
Nervous system disorders
Dizziness	8/21 (38.1%)	13
Renal and urinary disorders
Proteinuria	11/21 (52.4%)	14
Respiratory, thoracic and mediastinal disorders
Cough	1/21 (4.8%)	1
Dyspnea	4/21 (19%)	4
Pleural effusion	2/21 (9.5%)	2
Pneumonitis	3/21 (14.3%)	3
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysesthesia syndrm	2/21 (9.5%)	5
Rash maculo-papular	1/21 (4.8%)	2
Vascular disorders
Thromboembolic event	2/21 (9.5%)	2

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

All Principal Investigators ARE 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.