A Study of ENMD-2076 in Ovarian Clear Cell Cancers

• Sponsor: University Health Network, Toronto (Other)
• Overall Status: Completed
• CT.gov ID: NCT01914510
• Collaborator: (none)
• Enrollment: 40
• Locations: 6
• Arm: 1
• Duration (Months): 40
• Patients Per Site: 6.7
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

This is a phase 2 study to see how useful, safe, and tolerable an investigational drug called ENMD-2076 is in treating patients with ovarian clear cell carcinomas.

ENMD-2076 is an oral drug that works by blocking certain enzymes called Aurora A and tyrosine kinase from working. These enzymes are needed for cells to divide including cancer cells. ENMD-2076 also works by stopping the growth of new blood vessels which would provide the tumor with nutrients for it to grow. It is believed that by blocking Aurora A and tyrosine kinase enzymes from working and stopping new blood vessels from growing, the tumors may stop growing or shrink.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Clear Cell Carcinoma	Drug: ENMD-2076	Phase 2

Detailed Description

During the study, participants will be asked to take ENMD-2076 once a day, everyday. Every 28 days will be called a cycle. While receiving the study drug, participants will be asked to visit the clinic for tests and procedures. During Cycle 1, participants will be asked to visit the clinic about once a week and during Cycle 2 and future cycles, participants will be asked to visit the clinic on days 1 and 15. As a part of the study, tumor tissue (archival and fresh tumor biopsy) will be taken for biomarker research. When participants stop the study drug, they will be asked to have an end of study drug visit.

Study Design

• Study Type: Interventional
• Actual Enrollment: 40 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase II Study of Oral ENMD-2076 Administered to Patients With Ovarian Clear Cell Carcinomas
• Study Start Date: Sep 1, 2013
• Actual Primary Completion Date: Jan 1, 2017
• Actual Study Completion Date: Jan 1, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: ENMD-2076 ENMD-2067 will be taken orally at a dose of 275 mg, once a day, everyday. Patients with a body surface area of less than 1.65 m2 will receive a starting dose of 250 mg, once a day, everyday.	Drug: ENMD-2076

Outcome Measures

Primary Outcome Measures

1. Six Month Progression Free Survival Rate [Response will be determined based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1. Progression free survival is the time from the first day of treatment to the first observation of disease progression or Death/last F/U.]

   Progression Free Survival (PFS) is defined as the time from first day of treatment to the first observation of disease progression or death due to any cause or last follow up. PFS will be censored for patients who are alive and free of progression at time of last follow-up.

2. Complete or Partial Response Rate [2 years]

   Percentage of patients with complete or partial response as per RECIST 1.1 criteria.

Secondary Outcome Measures

1. Time to Disease Progression [2 years]

   Length of time until disease progression in patients treated with ENMD-2076

2. Levels of Certain Proteins and Gene Expression Compared to Patient Outcome Following Treatment [2 years]

   Association of somatic mutations in PIK3CA, ARID1A and PTEN mutation status, and ARID1A and PTEN expression assessed in archival samples and tumour biopsies with tumour response and patient outcome following treatment with ENMD 2076.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Have histologically documented diagnosis of ovarian clear cell carcinoma.

• Any number of prior chemotherapy regimens will be allowed but must include 1 line of platinum based therapy, and may include chemotherapy, biologics or other targeted therapies (except for Aurora A targeted therapies).

• Meet RECIST criteria (version 1.1) within 28 days of start of treatment by having measurable disease defined as one or more lesions that can be accurately measured in one or more dimensions. Areas of previous radiation may not serve as measurable disease unless there is evidence of progression post radiation.

• At time of registration, if the patient has had previous treatment it must have been at least 4 weeks since major surgery or radiation therapy; four weeks from any other previous anti-cancer therapy including biologics. Patients must have recovered from their treatment-related events with the exception of alopecia.

• Are ≥18 years of age

• Have clinically acceptable laboratory screening results within certain limits specified below:

• AST and ALT ≤ 2.5 times upper limit of normal (ULN) or less than or equal to 5 times ULN if liver metastases are present

• Total bilirubin ≤ 1.5 x ULN

• Creatinine ≤ 1.5 x UL

• Absolute neutrophil count ≥ 1500 cells/mm

• Platelets ≥ 150,000/mm3

• Hemoglobin ≥ 9.0 g/dl

• Have an ECOG performance status of ≤ 2

• Women of child-producing potential must agree to use effective contraceptive methods prior to study entry, during study participation, and for at least 30 days after the last administration of study medication. A serum pregnancy test within 72 hours prior to the initiation of therapy will be required for women of childbearing potential.

• Have the ability to understand the requirements of the study, provide written informed consent, abide by the study restrictions, and agree to return for the required assessments.

• Able to tolerate oral medication.

Exclusion Criteria:

• Women who are pregnant or nursing

• Have active, acute, or chronic clinically significant infections or bleeding.

• Have uncontrolled hypertension (systolic blood pressure greater than 150mmHg or diastolic blood pressure greater than 100mmHg); or history of congestive heart failure (equal to or greater than Grade 2).

• Have active angina pectoris, stroke, previous myocardial infarction within the past 12 months and not clinically stable, or any other pre-existing uncontrolled cardiovascular condition.

• Have chronic atrial fibrillation or QTc interval corrected for heart rate of greater than 470 msec.

• Have additional uncontrolled serious medical or psychiatric illness.

• Require therapeutic doses of anti-coagulation with warfarin or other coumarin derivatives. However, treatment with low molecular weight heparin (LMWH) is allowed.

• Known CNS metastases

• Have any medical condition that would impair the administration of oral agents including recurrent bowel obstructions, inflammatory bowel disease or uncontrolled nausea, vomiting or diarrhea

• Have persistent 2+ protein by urinalysis (patients with 2+ proteinuria that have a spot protein:creatinine ratio of less than 0.3 may be enrolled) or a history of nephrotic syndrome

• Have an active or history of additional malignancy which in the opinion of the study doctor would make assessment of outcome difficult.

• Require treatment with drugs known to be potent inducers or inhibitors of CYP3A4 at the time of registration

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Tom Baker Cancer Centre	Calgary	Alberta	Canada	T2N 4N2
2	Cross Cancer Institute	Edmonton	Alberta	Canada	T6G 1Z2
3	British Columbia Cancer Agency	Vancouver	Alberta	Canada	V5Z 4E6
4	London Regional Cancer Program	London	Ontario	Canada	N6A 4L6
5	Ottawa Regional Cancer Centre	Ottawa	Ontario	Canada	K1H 8L6
6	Princess Margaret Cancer Centre	Toronto	Ontario	Canada	M5G 2M9

Sponsors and Collaborators

• University Health Network, Toronto

Investigators

• Principal Investigator: Amit Oza, M.D., Princess Margaret Cancer Centre

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University Health Network, Toronto
• ClinicalTrials.gov Identifier: NCT01914510
• Other Study ID Numbers: ENMD-2076-OCC
• First Posted: Aug 2, 2013
• Last Update Posted: Dec 13, 2019
• Last Verified: Dec 1, 2019

• Keywords provided by University Health Network, Toronto: ovarian; cancer; clear cell; ENMD-2076; oral; capsule
• Additional relevant MeSH terms: Carcinoma; Adenomyoepithelioma; Adenocarcinoma, Clear Cell

Study Results

Participant Flow

Arm/Group Title	ENMD-2076
Arm/Group Description	ENMD-2067 will be taken orally at a dose of 275 mg, once a day, everyday, for the 28-day cycles. Patients with a body surface area of less than 1.65 m2 will receive a starting dose of 250 mg, once a day, everyday. Patients continue treatment until disease progression or unacceptable toxicity. Two dose reductions, 225mg and 150mg, are allowed (200mg and 150mg for patients with a body surface area under 1.65m2) and interruptions of therapy up to two weeks are permitted for recovery from toxicity or intercurrent illness.
Period Title: Overall Study
STARTED	40
COMPLETED	38
NOT COMPLETED	2

Baseline Characteristics

Arm/Group Title	ENMD-2076
Arm/Group Description	ENMD-2067 will be taken orally at a dose of 275 mg, once a day, everyday for 28 day cycles. Patients with a body surface area of less than 1.65 m2 will receive a starting dose of 250 mg, once a day, everyday for 28 day cycles. Patients can continue on therapy until disease progression or unacceptable toxicity. Dose reductions to 225mg and 150mg (200mg and 150mg for patients with body surface under 1.65m2) are permitted, with up to two weeks of therapy interruptions permitted for recovery from toxicity or intercurrent illness.
Overall Participants	38
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	54
Sex: Female, Male (Count of Participants)
Female	38 100%
Male	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%
Asian	11 28.9%
Native Hawaiian or Other Pacific Islander	0 0%
Black or African American	0 0%
White	26 68.4%
More than one race	0 0%
Unknown or Not Reported	1 2.6%
Prior Therapy (Count of Participants)
1 previous therapy	22 57.9%
2 previous therapies	12 31.6%
3 previous therapies	4 10.5%

Outcome Measures

1. Primary Outcome

Title	Six Month Progression Free Survival Rate
Description	Progression Free Survival (PFS) is defined as the time from first day of treatment to the first observation of disease progression or death due to any cause or last follow up. PFS will be censored for patients who are alive and free of progression at time of last follow-up.
Time Frame	Response will be determined based on Response Evaluation Criteria in Solid Tumors (RECIST) criteria 1.1. Progression free survival is the time from the first day of treatment to the first observation of disease progression or Death/last F/U.

Outcome Measure Data

Analysis Population Description

Of the 40 participants enrolled, 38 were deemed eligible for evaluation. Two patients did not complete one cycle of therapy and were considered not evaluable.

Arm/Group Title	ENMD-2076
Arm/Group Description	ENMD-2067 will be taken orally at a dose of 275 mg, once a day, everyday. Patients with a body surface area of less than 1.65 m2 will receive a starting dose of 250 mg, once a day, everyday. Patients will continue on therapy until disease progression or unacceptable toxicity. Dose reductions to 225mg and 150mg (200mg and 150mg for patients with body surface area under 1.65m2) are permitted, along with up to two weeks of therapy interruption for recovery from toxicity or intercurrent illness.
Measure Participants	38
Count of Participants [Participants]	8 21.1%

2. Primary Outcome

Title	Complete or Partial Response Rate
Description	Percentage of patients with complete or partial response as per RECIST 1.1 criteria.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Of the 40 participants enrolled onto trial, 38 were deemed eligible for evaluation. 2 patients did not complete a cycle of therapy and were considered ineligible for evaluation.

Arm/Group Title	ENMD-2076
Arm/Group Description	ENMD-2067 will be taken orally at a dose of 275 mg, once a day, everyday. Patients with a body surface area of less than 1.65 m2 will receive a starting dose of 250 mg, once a day, everyday. Patients will continue therapy until disease progression or unacceptable toxicity. Dose reductions to 225mg and 150mg (200mg and 150mg for patients with body surface area under 1.65m2) are permitted, along with up to two weeks of interrupted therapy for recovery from toxicities or intercurrent illness.
Measure Participants	38
Count of Participants [Participants]	3 7.9%

3. Secondary Outcome

Title	Time to Disease Progression
Description	Length of time until disease progression in patients treated with ENMD-2076
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Data not collected.

Arm/Group Title	ENMD-2076
Arm/Group Description	ENMD-2067 will be taken orally at a dose of 275 mg, once a day, everyday. Patients with a body surface area of less than 1.65 m2 will receive a starting dose of 250 mg, once a day, everyday. Patients will continue therapy until disease progression or unacceptable toxicity. Dose reductions to 225mg and 150mg (200mg and 150mg for patients with body surface area under 1.65m2) are permitted, along with up to two weeks of interrupted therapy for recovery from toxicities or intercurrent illness.
Measure Participants	0

4. Secondary Outcome

Title	Levels of Certain Proteins and Gene Expression Compared to Patient Outcome Following Treatment
Description	Association of somatic mutations in PIK3CA, ARID1A and PTEN mutation status, and ARID1A and PTEN expression assessed in archival samples and tumour biopsies with tumour response and patient outcome following treatment with ENMD 2076.
Time Frame	2 years

Outcome Measure Data

Analysis Population Description

Data not collected

Arm/Group Title	ENMD-2076
Arm/Group Description	ENMD-2067 will be taken orally at a dose of 275 mg, once a day, everyday. Patients with a body surface area of less than 1.65 m2 will receive a starting dose of 250 mg, once a day, everyday. Patients will continue therapy until disease progression or unacceptable toxicity. Dose reductions to 225mg and 150mg (200mg and 150mg for patients with body surface area under 1.65m2) are permitted, along with up to two weeks of interrupted therapy for recovery from toxicities or intercurrent illness.
Measure Participants	0

Adverse Events

Time Frame	All AEs will be recorded in the source documents. All AEs, including clinically significant abnormal laboratory AEs, will be entered in the electronic CRFs from the time of the first dose of study medication until up to 30 days after the end of study drug administration or until alternate therapy is initiated, whichever occurs first.
Arm/Group Title	ENMD-2076
Arm/Group Description	ENMD-2067 will be taken orally at a dose of 275 mg, once a day, everyday. Patients with a body surface area of less than 1.65 m2 will receive a starting dose of 250 mg, once a day, everyday. Patients will continue on therapy until disease progression or unacceptable toxicity. Dose reductions to 225mg and 150mg (200mg and 150mg for patients with body surface area under 1.65m2) are permitted, along with up to two weeks of therapy interruption for recovery from toxicity or intercurrent illness.
All Cause Mortality
	ENMD-2076
	Affected / at Risk (%)	# Events
Total	0/40 (0%)
Serious Adverse Events
	ENMD-2076
	Affected / at Risk (%)	# Events
Total	10/40 (25%)
Cardiac disorders
Hypertension	2/40 (5%)	3
Gastrointestinal disorders
Abdominal Pain	1/40 (2.5%)	2
Nausea & Vomiting	1/40 (2.5%)	1
General disorders
Dehydration	1/40 (2.5%)	1
Dyaphagia	1/40 (2.5%)	1
Psychiatric disorders
Confusion	2/40 (5%)	2
Reproductive system and breast disorders
Vaginal Fistula	1/40 (2.5%)	1
Respiratory, thoracic and mediastinal disorders
Pulmonary Embolism	1/40 (2.5%)	1
Other (Not Including Serious) Adverse Events
	ENMD-2076
	Affected / at Risk (%)	# Events
Total	40/40 (100%)
Blood and lymphatic system disorders
Hypoalbuminemia	15/40 (37.5%)	15
Anemia	13/40 (32.5%)	13
Alkaline Phosphatase Increase	11/40 (27.5%)	11
White Blood Cell Decrease	9/40 (22.5%)	9
Hypocalcemia	9/40 (22.5%)	9
AST Increased	7/40 (17.5%)	7
Hypophosphatemia	6/40 (15%)	6
ALT Increased	6/40 (15%)	6
Hyponatremia	4/40 (10%)	4
Endocrine disorders
Elevated TSH	9/40 (22.5%)	9
Hypothyroidism	8/40 (20%)	8
Gastrointestinal disorders
Nausea	27/40 (67.5%)	27
Constipation	23/40 (57.5%)	23
Diarrhea	20/40 (50%)	20
Vomiting	16/40 (40%)	16
General disorders
Fatigue	28/40 (70%)	28
Headache	18/40 (45%)	18
Weight Loss	15/40 (37.5%)	15
Mucositis	8/40 (20%)	8
Metabolism and nutrition disorders
Hypomagnesemia	19/40 (47.5%)	19
Nervous system disorders
Dysguesia	10/40 (25%)	10
Dizziness	9/40 (22.5%)	9
Renal and urinary disorders
Proteinuria	14/40 (35%)	14
Skin and subcutaneous tissue disorders
Palmar-Plantar Erythrodysesthensia	10/40 (25%)	10

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.