Carboplatin/Pralatrexate in Recurrent Platinum-Sensitive Ovarian, Fallopian or Primary Peritoneal Cancer

• Sponsor: Massachusetts General Hospital (Other)
• Overall Status: Completed
• CT.gov ID: NCT01188876
• Collaborator: Dana-Farber Cancer Institute (Other), Brigham and Women's Hospital (Other), National Comprehensive Cancer Network (Other)
• Enrollment: 50
• Locations: 2
• Arm: 1
• Duration (Months): 83
• Patients Per Site: 25
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

Pralatrexate is a type of antifolate drug which means is restrains the production of folic acid in the body. Folic acids are used by tumors to increase tumor cell growth and division. It is believed that reducing folic acid will hinder the rapid division of tumor cells, their growth and production. Carboplatin is an FDA approved chemotherapy drug for ovarian, fallopian tube and primary peritoneal cancer. Some antifolate drugs are used with other chemotherapy drugs to enhance cancer-fighting characteristics. It is believed that the study drug pralatrexate may improve the anti-tumor effect of carboplatin. In this research study we are looking for the highest dose of pralatrexate that can be given safely in combination with carboplatin.

Condition or Disease	Intervention/Treatment	Phase
Ovarian Cancer; Fallopian Tube Cancer; Peritoneal Cancer	Drug: carboplatin; Drug: pralatrexate; Drug: Folic Acid; Drug: Vitamin B12 Injection	Phase 1/Phase 2

Detailed Description

• Since we are looking for the highest dose of the study drug that can be administered safely without severe or unmanageable side effects, not everyone who participates will receive the same dose of the study drug.

• Each study cycle will last 28 days. On Day 1, participants will receive carboplatin intravenously. On Days 1 and 15 of each cycle they will receive pralatrexate intravenously. Participants will also be asked to take folic acid orally on a daily basis starting 7 days before the first dose of pralatrexate and continuing until 30 days after the last dose of pralatrexate. They will also receive a vitamin B12 injection no more than 10 weeks prior to the first dose of pralatrexate and every 8-10 weeks after the first dose of pralatrexate.

• Participants will come to the clinic on Day 1 and 15 of each cycle and have the following tests/procedures performed: Medical history; Vital signs; Blood tests, assessment of the tumor (every two cycles) and an EKG (before the start of cycle 2).

• In addition, during Cycle 1, participants will come to the clinic weekly for blood tests.

• Pharmacokinetic (PK) blood samples (to monitor how the body absorbs and breaks down the study drug) will be done at the following time points during Cycle 1: Day 1-3 and Day 15-17.

• Participants will be asked to take the study drugs for up to 6 cycles. They may continue beyond 6 cycles as long as there is evidence that the tumor is not growing and they are not experiencing any unacceptable side effects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 50 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Study of Carboplatin and Pralatrexate in Patients With Recurrent Platinum-Sensitive Ovarian, Fallopian or Primary Peritoneal Cancer
• Study Start Date: Aug 1, 2010
• Actual Primary Completion Date: Jul 1, 2016
• Actual Study Completion Date: Jul 1, 2017

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Carboplatin/Pralatrexate

Drug: carboplatin; Given intravenously on Day 1 of each 28-day cycle; Drug: pralatrexate; Given intravenously on Day 1 and Day 15 of each 28-day cycle.; Drug: Folic Acid; Given orally on a daily basis starting 7 days before the first dose of pralatrexate and continuing until 30 days after the last dose of pralatrexate.; Drug: Vitamin B12 Injection; Given vitamin B12 injection no more than 10 weeks prior to the first dose of pralatrexate and every 8-10 weeks after the first dose of pralatrexate.

Outcome Measures

Primary Outcome Measures

1. Maximum Tolerated Dose (MTD) [1 year]

   The maximum tolerated dose of Pralatrexate in combination with Carboplatin in this patient population. The unit is given in milligrams per square meter of body surface area. MTD was determined using a standard 3 + 3 dose escalation cohort, where 3 participants were enrolled on the starting dose of 30 mg/m2 and if no dose limiting toxicities (DLT) were experienced after a full cycle, 3 additional participants were enrolled at the next highest dose level. Each increase in dose level escalated the dose of Pralatrexate by 15 mg/m2. If during any dose level, 1 patient out of 3 develops a DLT, then 3 additional patients will be added to that dose level. If 2 out of the 3 patients placed on any dose level experience a DLT, the preceding dose is considered MTD. If 1/6 has a DLT, the next higher dose level will commence accrual (unless at level +5 and then accrual to the Phase I portion will stop). If ≥ 2 of 6 patients have a DLT, then the preceding dose will be considered MTD.

2. Best Overall Response [1 Year]

   Summary of the best overall responses to treatment as assessed by RECIST (Response Evaluation Criteria In Solid Tumors). Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions

Secondary Outcome Measures

1. Overall Survival [6, 12, 18, and 24 months]

   The number of participants still alive at the given time points. The duration of time is measured from the start of treatment until death due to any cause, participants are censored at the date of the last evaluation. The number participants surviving at 6, 12, 18, and 24 months is shown.

2. Progression Free Survival [3 months, 6 months]

   The number of participants alive and without disease progression at the given time-points. Time is measured from the start of treatment. Progression is defined as having at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.

3. Treatment Related Adverse Events [1 Year]

   Summary of the treatment related adverse events experienced by participants as assessed by Common Terminology Criteria for Adverse Events (CTCAE 4). Adverse events were assessed from the start of treatment until 30 days after the last dose of study drug.

4. Maximum Concentration of Drug in Plasma (Cmax) [Day 1 and Day 15]

   The maximum concentration of Pralatrexate at day 1 and 15 among phase 1 participants dosed at 105 milligrams per square meter of body surface area (mg/m2). The concentration is given in micrograms per milliliter.

5. Area Under the Plasma Drug Concentration-Time Curve (AUC) [Day 1 and Day 15]

   Area under the plasma drug concentration-time curve (AUC) for phase 1 participants that were dosed at 105 mg/m2. AUC represents the actual body exposure to drug after administration of a dose of the drug and is expressed in micrograms * hour per milliliter (ug*h/mL).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Patients must be diagnosed with a platinum-sensitive recurrence of epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer.

• The following histologic subtypes are eligible: papillary serous, endometrioid, mucinous, clear cell, adenocarcinomas, transitional, and mixtures of the above.

• Patients must have at least one measurable lesion according to RECIST criteria via CT or MRI scan. CT of the chest should be performed if any known disease is present in the chest. Pleural effusions, ascites, bone metastases, CA125 tumor markers, and lesions located in previously radiated areas are not considered measurable.

• Patients must have received a platinum-containing regimen at initial diagnosis.

• ECOG Performance Status of 0, 1 or 2

• Patients may have received up to 2 prior chemotherapy regimens in the recurrent cancer setting

• 18 years of age or older

• Life expectancy of greater than 12 weeks

• Baseline laboratory values must meet what is outlined in the protocol

• Patients must receive vitamin B12 and folic acid prior to starting treatment

• Complete recovery from previous chemotherapy or biologic therapy

• During the Phase II of the study, patients with significant ascites and/or pleural effusions will undergo consideration of drainage of these areas prior to starting carboplatin and pralatrexate.

• Women of childbearing potential must have a negative pregnancy test within 7 days prior to initiating chemotherapy on trial and must agree to practice effective method of birth control during the study and for six months after their last treatment.

• Patients must have a normal QTc interval

Exclusion Criteria:

• Prior pelvic radiotherapy to greater than 25% of bone marrow

• Any uncontrolled medical problem that in the opinion of the investigator would preclude safe administration of the study drugs.

• Past history of bone marrow transplantation or stem cell support

• Patient with known history of CNS metastasis is ineligible unless the patient has had treatment with surgery or radiation therapy, is neurologically stable, and does not require oral or intravenous corticosteroids or anticonvulsants.

• A history of prior malignancy except for adequately treated carcinoma in situ of the uterine cervix, incidental stage I endometrial cancer, basal cell or squamous cell skin cancer, or breast cancer (invasive or ductal carcinoma in situ) for which the patient has been disease-free for at least three years.

• Routine prophylactic use of G-CSF or GM-CSF within two weeks prior to study entry.

• Clinically significant cardiac disease

• Uncontrolled hypercalcemia or diabetes mellitus

• Any signs of intestinal obstruction that interfere with bowel function and/or nutrition

• Grade 2 or greater peripheral neuropathy

• Participation in an investigational study within three weeks prior to study entry.

• History of anaphylactic shock to prior platinum chemotherapy that would preclude safe administration of study carboplatin.

• History of psychiatric disability or other central nervous system disorder as judged by the principal investigator that would be considered significant and that would preclude informed consent, safe administration of study medications and affecting ability to comply with study procedures.

• Doses of ibuprofen in excess of 400mg QID.

• Interval cytoreductive surgery planned for while subject is on-study.

• Recurrence/progression within 6 months of receiving ay platinum regimen

• Patients with either pleural effusions or ascites are not eligible for Phase I of the study

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Massachusetts General Hospital	Boston	Massachusetts	United States	02114
2	Dana-Farber Cancer Institute	Boston	Massachusetts	United States	02115

Sponsors and Collaborators

• Massachusetts General Hospital
• Dana-Farber Cancer Institute
• Brigham and Women's Hospital
• National Comprehensive Cancer Network

Investigators

• Principal Investigator: Marcela G. del Carmen, MD, MPH, Massachusetts General Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Marcela G. del Carmen, MD, MD, MPH, Massachusetts General Hospital
• ClinicalTrials.gov Identifier: NCT01188876
• Other Study ID Numbers: 10-113
• First Posted: Aug 26, 2010
• Last Update Posted: Jan 19, 2018
• Last Verified: Dec 1, 2017

• Keywords provided by Marcela G. del Carmen, MD, MD, MPH, Massachusetts General Hospital: carboplatin; recurrent; platinum sensitive; pralatrexate
• Additional relevant MeSH terms: Fallopian Tube Neoplasms; Peritoneal Neoplasms; Hypersensitivity; Folic Acid; Vitamin B 12; Hydroxocobalamin; Carboplatin

Study Results

Participant Flow

Arm/Group Title	Carboplatin/Pralatrexate
Arm/Group Description	carboplatin: Given intravenously on Day 1 of each 28-day cycle pralatrexate: Given intravenously on Day 1 and Day 15 of each 28-day cycle.
Period Title: Overall Study
STARTED	50
COMPLETED	50
NOT COMPLETED	0

Baseline Characteristics

Arm/Group Title	Carboplatin/Pralatrexate
Arm/Group Description	carboplatin: Given intravenously on Day 1 of each 28-day cycle pralatrexate: Given intravenously on Day 1 and Day 15 of each 28-day cycle.
Overall Participants	50
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	59
Sex: Female, Male (Count of Participants)
Female	50 100%
Male	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	0 0%
Not Hispanic or Latino	49 98%
Unknown or Not Reported	1 2%
Race/Ethnicity, Customized (Count of Participants)
White	48 96%
Black or African American	1 2%
Other	1 2%
Region of Enrollment (Count of Participants)
United States	50 100%
ECOG Performance Status (Count of Participants)
0	34 68%
1	16 32%
Primary Site (Count of Participants)
Ovary	34 68%
Fallopian Tube	6 12%
Peritoneal	5 10%
Other	5 10%
Histology Subtype (Count of Participants)
Serous	30 60%
Endometrioid	6 12%
Transitional Cell	1 2%
Carcinosarcoma	3 6%
Other	10 20%

Outcome Measures

1. Primary Outcome

Title	Maximum Tolerated Dose (MTD)
Description	The maximum tolerated dose of Pralatrexate in combination with Carboplatin in this patient population. The unit is given in milligrams per square meter of body surface area. MTD was determined using a standard 3 + 3 dose escalation cohort, where 3 participants were enrolled on the starting dose of 30 mg/m2 and if no dose limiting toxicities (DLT) were experienced after a full cycle, 3 additional participants were enrolled at the next highest dose level. Each increase in dose level escalated the dose of Pralatrexate by 15 mg/m2. If during any dose level, 1 patient out of 3 develops a DLT, then 3 additional patients will be added to that dose level. If 2 out of the 3 patients placed on any dose level experience a DLT, the preceding dose is considered MTD. If 1/6 has a DLT, the next higher dose level will commence accrual (unless at level +5 and then accrual to the Phase I portion will stop). If ≥ 2 of 6 patients have a DLT, then the preceding dose will be considered MTD.
Time Frame	1 year

Outcome Measure Data

Analysis Population Description

The participants that participated in the phase 1 dose escalation portion of the study

Arm/Group Title	Carboplatin/Pralatrexate
Arm/Group Description	carboplatin: Given intravenously on Day 1 of each 28-day cycle pralatrexate: Given intravenously on Day 1 and Day 15 of each 28-day cycle.
Measure Participants	30
Number [mg/m^2]	105

2. Primary Outcome

Title	Best Overall Response
Description	Summary of the best overall responses to treatment as assessed by RECIST (Response Evaluation Criteria In Solid Tumors). Complete Response (CR): Disappearance of all target lesions Partial Response (PR): At least a 30% decrease in the sum of the longest diameter (LD) of target lesions, taking as reference the baseline sum LD Stable Disease (SD): Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum LD since the treatment started Progressive Disease (PD): At least a 20% increase in the sum of the LD of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carboplatin/Pralatrexate
Arm/Group Description	carboplatin: Given intravenously on Day 1 of each 28-day cycle pralatrexate: Given intravenously on Day 1 and Day 15 of each 28-day cycle.
Measure Participants	50
Complete Response	0 0%
Partial Response	19 38%
Stable Disease	24 48%
Progressive Disease	5 10%
Unevaluable	2 4%

3. Secondary Outcome

Title	Overall Survival
Description	The number of participants still alive at the given time points. The duration of time is measured from the start of treatment until death due to any cause, participants are censored at the date of the last evaluation. The number participants surviving at 6, 12, 18, and 24 months is shown.
Time Frame	6, 12, 18, and 24 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carboplatin/Pralatrexate
Arm/Group Description	carboplatin: Given intravenously on Day 1 of each 28-day cycle pralatrexate: Given intravenously on Day 1 and Day 15 of each 28-day cycle.
Measure Participants	50
6 Months	49 98%
12 Months	49 98%
18 Months	46 92%
24 Months	33 66%

4. Secondary Outcome

Title	Progression Free Survival
Description	The number of participants alive and without disease progression at the given time-points. Time is measured from the start of treatment. Progression is defined as having at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions.
Time Frame	3 months, 6 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carboplatin/Pralatrexate
Arm/Group Description	carboplatin: Given intravenously on Day 1 of each 28-day cycle pralatrexate: Given intravenously on Day 1 and Day 15 of each 28-day cycle.
Measure Participants	50
3 Months	44 88%
6 Months	40 80%

5. Secondary Outcome

Title	Treatment Related Adverse Events
Description	Summary of the treatment related adverse events experienced by participants as assessed by Common Terminology Criteria for Adverse Events (CTCAE 4). Adverse events were assessed from the start of treatment until 30 days after the last dose of study drug.
Time Frame	1 Year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carboplatin/Pralatrexate
Arm/Group Description	carboplatin: Given intravenously on Day 1 of each 28-day cycle pralatrexate: Given intravenously on Day 1 and Day 15 of each 28-day cycle.
Measure Participants	50
Constipation	2 4%
Mucositis	13 26%
Nausea	16 32%
Vomiting	2 4%
Diarrhea	1 2%
Anemia	5 10%
Thrombocytopenia	8 16%
Neutropenia	6 12%
Febrile neutropenia	2 4%
Hypersensitivity reaction	17 34%
Hypomagnesemia	3 6%
Pruritis	1 2%
Rash	3 6%
Fatigue	15 30%

6. Secondary Outcome

Title	Maximum Concentration of Drug in Plasma (Cmax)
Description	The maximum concentration of Pralatrexate at day 1 and 15 among phase 1 participants dosed at 105 milligrams per square meter of body surface area (mg/m2). The concentration is given in micrograms per milliliter.
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

Participants that required a dose reduction due to an adverse event were excluded from the day 15 evaluation

Arm/Group Title	Carboplatin/Pralatrexate
Arm/Group Description	carboplatin: Given intravenously on Day 1 of each 28-day cycle pralatrexate: Given intravenously on Day 1 and Day 15 of each 28-day cycle.
Measure Participants	17
Day 1	23.87
Day 15	17.61

7. Secondary Outcome

Title	Area Under the Plasma Drug Concentration-Time Curve (AUC)
Description	Area under the plasma drug concentration-time curve (AUC) for phase 1 participants that were dosed at 105 mg/m2. AUC represents the actual body exposure to drug after administration of a dose of the drug and is expressed in micrograms * hour per milliliter (ug*h/mL).
Time Frame	Day 1 and Day 15

Outcome Measure Data

Analysis Population Description

Participants that required a dose reduction due to an adverse event were excluded from the day 15 evaluation

Arm/Group Title	Carboplatin/Pralatrexate
Arm/Group Description	carboplatin: Given intravenously on Day 1 of each 28-day cycle pralatrexate: Given intravenously on Day 1 and Day 15 of each 28-day cycle.
Measure Participants	17
Day 1	9.89
Day 15	8.01

Adverse Events

Time Frame	Adverse events information was collected from the start of treatment until 30 days after the last dose of study medication was received (median duration of 7 months)
Arm/Group Title	Carboplatin/Pralatrexate
Arm/Group Description	carboplatin: Given intravenously on Day 1 of each 28-day cycle pralatrexate: Given intravenously on Day 1 and Day 15 of each 28-day cycle.
All Cause Mortality
	Carboplatin/Pralatrexate
	Affected / at Risk (%)	# Events
Total	0/50 (0%)
Serious Adverse Events
	Carboplatin/Pralatrexate
	Affected / at Risk (%)	# Events
Total	4/50 (8%)
Blood and lymphatic system disorders
Febrile Neutropenia	2/50 (4%)	2
Thrombocytopenia	2/50 (4%)	2
Thromboembolytic event	1/50 (2%)	1
Gastrointestinal disorders
Mucositis Oral	1/50 (2%)	1
Dyspepsia	1/50 (2%)	1
Other (Not Including Serious) Adverse Events
	Carboplatin/Pralatrexate
	Affected / at Risk (%)	# Events
Total	50/50 (100%)
Blood and lymphatic system disorders
Anemia	16/50 (32%)	29
Febrile neutropenia	5/50 (10%)	7
Ear and labyrinth disorders
Tinnitus	3/50 (6%)	3
Eye disorders
Watering eyes	6/50 (12%)	6
Gastrointestinal disorders
Abdominal distension	3/50 (6%)	3
Abdominal pain	15/50 (30%)	19
Bloating	3/50 (6%)	3
Colonic obstruction	3/50 (6%)	3
Constipation	21/50 (42%)	32
Diarrhea	11/50 (22%)	15
Gastritis	3/50 (6%)	3
Gastroesophageal reflux disease	7/50 (14%)	7
Gastrointestinal disorders - Other, specify	3/50 (6%)	3
Mucositis oral	24/50 (48%)	53
Nausea	34/50 (68%)	61
Vomiting	13/50 (26%)	19
General disorders
Fatigue	40/50 (80%)	63
Fever	5/50 (10%)	5
General disorders and administration site conditions - Other, specify	3/50 (6%)	3
Pain	4/50 (8%)	5
Immune system disorders
Allergic reaction	14/50 (28%)	15
Anaphylaxis	3/50 (6%)	3
Infections and infestations
Upper respiratory infection	4/50 (8%)	4
Urinary tract infection	6/50 (12%)	10
Injury, poisoning and procedural complications
Bruising	3/50 (6%)	3
Investigations
Alanine aminotransferase increased	3/50 (6%)	3
Alkaline phosphatase increased	3/50 (6%)	3
Creatinine increased	3/50 (6%)	4
Neutrophil count decreased	18/50 (36%)	25
Platelet count decreased	19/50 (38%)	36
White blood cell decreased	5/50 (10%)	8
Metabolism and nutrition disorders
Anorexia	4/50 (8%)	5
Hyperglycemia	3/50 (6%)	7
Hypocalcemia	3/50 (6%)	3
Hypokalemia	5/50 (10%)	5
Hypomagnesemia	22/50 (44%)	35
Musculoskeletal and connective tissue disorders
Arthralgia	3/50 (6%)	3
Back pain	7/50 (14%)	7
Bone pain	3/50 (6%)	4
Flank pain	3/50 (6%)	3
Musculoskeletal and connective tissue disorder - Other, specify	3/50 (6%)	4
Pain in extremity	5/50 (10%)	5
Nervous system disorders
Headache	3/50 (6%)	4
Nervous system disorders - Other, specify	3/50 (6%)	4
Peripheral motor neuropathy	3/50 (6%)	4
Peripheral sensory neuropathy	12/50 (24%)	12
Psychiatric disorders
Anxiety	9/50 (18%)	9
Depression	5/50 (10%)	5
Insomnia	3/50 (6%)	4
Reproductive system and breast disorders
Pelvic pain	3/50 (6%)	3
Respiratory, thoracic and mediastinal disorders
Cough	10/50 (20%)	13
Epistaxis	6/50 (12%)	7
Sore throat	6/50 (12%)	10
Skin and subcutaneous tissue disorders
Alopecia	5/50 (10%)	5
Rash acneiform	4/50 (8%)	5
Vascular disorders
Hypertension	5/50 (10%)	6

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.