Abraxane and Alimta in Advanced Solid Tumors

• Sponsor: University of California, Davis (Other)
• Overall Status: Terminated
• CT.gov ID: NCT00470548
• Collaborator: Celgene (Industry), Eli Lilly and Company (Industry)
• Enrollment: 49
• Location: 1
• Arms: 2
• Duration (Months): 90
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

RATIONALE: Drugs used in chemotherapy, such as paclitaxel albumin-stabilized nanoparticle formulation, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Pemetrexed may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving paclitaxel albumin-stabilized nanoparticle formulation together with pemetrexed may kill more tumor cells.

PURPOSE: This phase I/II trial is studying the side effects and best dose of paclitaxel albumin-stabilized nanoparticle formulation when given together with pemetrexed and to see how well they work in treating patients with advanced non-small cell lung cancer, breast cancer, or other solid tumors.

Condition or Disease	Intervention/Treatment	Phase
Breast Cancer; Lung Cancer; Unspecified Adult Solid Tumor, Protocol Specific	Drug: Abraxane; Drug: Alimta	Phase 1/Phase 2

Detailed Description

OBJECTIVES:

Primary

• Determine the safety of paclitaxel albumin-stabilized nanoparticle formulation when administered with pemetrexed disodium in patients with advanced non-small cell lung cancer, breast cancer, or other solid tumors. (Phase I)

• Determine the efficacy of this regimen, as measured by objective tumor response rate (RECIST criteria), in these patients. (Phase II)

Secondary

• Determine the preliminary efficacy of paclitaxel albumin-stabilized nanoparticle formulation and pemetrexed disodium in these patients. (Phase I)

• Determine the overall survival of patients treated with this regimen. (Phase II)

• Evaluate the frequency and severity of toxicities associated with this regimen. (Phase II)

OUTLINE: This is a phase I, dose-escalation study of paclitaxel albumin-stabilized nanoparticle formulation followed by an open-label, phase II study.

• Phase I: Patients receive pemetrexed disodium IV over 10 minutes and paclitaxel albumin-stabilized nanoparticle formulation IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Cohorts of 3-6 patients receive escalating doses of paclitaxel albumin-stabilized nanoparticle formulation until the maximum tolerated dose (MTD) is determined. The MTD is defined as the dose preceding that at which 2 of 3 or 2 of 6 patients experience dose-limiting toxicity.

• Phase II: Patients receive pemetrexed disodium and paclitaxel albumin-stabilized nanoparticle formulation at the MTD as in phase I.

After completion of study treatment, patients are followed periodically.

Study Design

• Study Type: Interventional
• Actual Enrollment: 49 participants
• Allocation: Non-Randomized
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase I/II Trial of Abraxane® (ABI-007) and Alimta® (Pemetrexed) in Advanced Solid Tumors With Emphasis on Non-Small Cell Lung Cancer (NSCLC) and Breast Cancer
• Study Start Date: Apr 1, 2007
• Actual Primary Completion Date: Oct 1, 2014
• Actual Study Completion Date: Oct 1, 2014

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Phase I: Abraxane and Alimta Three dose levels were tested. Pemetrexed 500mg/m2 day 1 and nab-paclitaxel day 1 at 180, 220, and 260 mg/m2 every 21 days.	Drug: Abraxane; ABI-007 IV administration following pemetrexed on Day 1 of each cycle (infused over 30 minutes); Other Names: paclitaxel albumin-stabilized nanoparticle formulation ABI-007 ; Drug: Alimta; Pemetrexed IV administration on Day 1 of each cycle (infused over 10 minutes); Other Names: pemetrexed disodium
Experimental: Phase II: Abraxane and Alimta Pemetrexed 500mg/m2 day 1 and nab-paclitaxel day 1 at 260 mg/m2 every 21 days.	Drug: Abraxane; ABI-007 IV administration following pemetrexed on Day 1 of each cycle (infused over 30 minutes); Other Names: paclitaxel albumin-stabilized nanoparticle formulation ABI-007 ; Drug: Alimta; Pemetrexed IV administration on Day 1 of each cycle (infused over 10 minutes); Other Names: pemetrexed disodium

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose Limiting Toxicities [Up to21 days]

   Dose limiting toxicity (DLT) was defined as any of the following occurring during the first cycle: Grade 4 thrombocytopenia, or grade 3 thrombocytopenia associated with bleeding, requirement for transfusion, febrile neutropenia, neutropenia with documented infection. Non-hematologic DLT included any other ≥ grade 3 non-hematologic toxicity that was clinically significant and considered by the investigator to be related to study drug. Alopecia and grade 3 allergic reaction/hypersensitivity with infusion were not considered DLTs.

2. Number of Patients With Toxicities [Up to 1 year]

   Toxicities was evaluated based on the standard NCI CTCAE Version 3.0 grading criteria. Attributable grade ≥ 3 hematologic and non-hematologic toxicities are presented here.

Secondary Outcome Measures

1. Duration of Overall Survival [Up to 2 years]

   From time of enrollment to the first observation of disease progression or death.

2. Number of Participants With Complete Response [Up to 2 years]

   Per RECIST criteria, complete response (CR) is defined as the disappearance of all target lesions.

3. Number of Participants With Stable Disease [Up to 2 years]

   Stable Disease is measured from the start of the treatment until the criteria for disease progression are met. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions

4. Number of Participants With Partial Response [Up to 2 years]

   At least a 30% decrease in the sum of the longest diameter of target lesions

5. Number of Participants With Disease Control [Up to 2 years]

   Disease control is complete response plus partial response plus stable disease from the start of treatment to death or disease progression.

Eligibility Criteria

Criteria

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

Inclusion Criteria

1. For the phase II portion patients must have cytologically or histologically proven selected stage IIIB (pleural effusion) or IV NSCLC.

2. For the phase II portion patients must have NSCLC that has progressed or recurred after treatment with platinum-based therapy.

3. No prior pemetrexed. Prior Taxol is allowed. Prior ABI 007 is not allowed.

4. Patients must have measurable disease by RECIST criteria for the phase II portion.

5. Patients must be 18 years of age or older.

6. Patients must have a performance status of 0 -2

7. Patients must have an estimated survival of at least 3 months.

8. Any prior chemotherapy must have been completed at least 4 weeks prior to start of treatment.

9. Patients must have adequate renal function as documented by a calculated creatinine clearance of > 45 ml/min

10. Patients must have adequate liver functions: AST and ALT < 2.5 X upper limit of normal, and bilirubin < upper limit of normal.

11. Patients must have adequate bone marrow function: Platelets >100,000 cells/mm3 and ANC

1,500 cells/mm3.

1. For patients who have baseline clinically significant pleural or peritoneal effusions (on the basis of symptoms or clinical examination) before initiation of pemetrexed therapy, consideration should be given to draining the effusion prior to dosing.

2. Patients with asymptomatic treated brain metastasis (surgical resection or radiotherapy) may be included if they are neurologically stable and have been off steroids and anticonvulsants for at least 4 weeks.

3. Patients must be able to take and retain oral medication.

4. Ability to take folic acid, vitamin B12 and dexamethasone according to protocol.

5. Ability to interrupt NSAIDS 2 days before, the day of, and 2 days following administration of pemetrexed.

6. Patients of reproductive potential must agree to use effective contraceptive method while on treatment and for 3 months afterwards as the effects of these drugs on the unborn fetus are unknown.

7. No other current active malignancy.

8. Patient or his/her legally authorized representative or guardian signed the Informed Consent form prior to participation in any study-related activities.

Exclusion Criteria

1. Pregnant or breastfeeding women.

2. Patient with pre-existing peripheral neuropathy of NCI CTCAE Version 3.0 of grade 2.

3. Patient has a clinically significant concurrent illness.

4. Patient is currently enrolled in a different clinical study in which investigational procedures are performed or investigational therapies are administered.

5. Patient has a history of allergy or hypersensitivity to the study drugs or a taxane.

6. Patient has serious medical risk factors involving any of the major organ systems such that the investigator considers it unsafe for the patient to receive an experimental research drug.

7. Prior therapy with pemetrexed, or ABI-007.

8. Patient is receiving treatment with any excluded concomitant medication.

9. Presence of third space fluid which cannot be controlled by drainage.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of California Davis Cancer Center	Sacramento	California	United States	95817

Sponsors and Collaborators

• University of California, Davis
• Celgene
• Eli Lilly and Company

Investigators

• Study Chair: David R. Gandara, MD, University of California, Davis

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: University of California, Davis
• ClinicalTrials.gov Identifier: NCT00470548
• Other Study ID Numbers: UCDCC#185; 224355; ABX027; H3E-US-I017
• First Posted: May 7, 2007
• Last Update Posted: Jan 10, 2018
• Last Verified: Jan 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by University of California, Davis: male breast cancer; recurrent breast cancer; stage IIIA breast cancer; stage IIIB breast cancer; stage IIIC breast cancer; stage IV breast cancer; stage IIIA non-small cell lung cancer; stage IIIB non-small cell lung cancer; stage IV non-small cell lung cancer; recurrent non-small cell lung cancer; unspecified adult solid tumor, protocol specific
• Additional relevant MeSH terms: Breast Neoplasms; Lung Neoplasms; Paclitaxel; Pemetrexed; Albumin-Bound Paclitaxel

Study Results

Participant Flow

Arm/Group Title	Phase I: Dose Level 1	Phase I: Dose Level 2	Phase I: Dose Level 3	Phase II
Arm/Group Description	Pemetrexed 500 mg/m2 plus Abraxane 180 mg/m2	Pemetrexed 500 mg/m2 plus Abraxane 220 mg/m2	Pemetrexed 500 mg/m2 plus Abraxane 260 mg/m2	Pemetrexed 500 mg/m2 plus Abraxane 260 mg/m2
Period Title: Overall Study
STARTED	3	3	6	37
COMPLETED	3	3	6	37
NOT COMPLETED	0	0	0	0

Baseline Characteristics

Arm/Group Title	Phase I: Abraxane and Pemetrexed	Phase II: Abraxane and Pemetrexed	Total
Arm/Group Description	A 3 + 3 dose escalation design was used to determine the maximum tolerated dose and the recommended phase II dose. Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 180 mg/m2, 220 mg/m2 and 260 mg/m2 IV administration following pemetrexed on Day 1 of each cycle .	Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 260 mg/m2IV administration following pemetrexed on Day 1 of each cycle	Total of all reporting groups
Overall Participants	12	37	49
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	70	63	63
Sex: Female, Male (Count of Participants)
Female	5 41.7%	14 37.8%	19 38.8%
Male	7 58.3%	23 62.2%	30 61.2%
Region of Enrollment (Count of Participants)
United States	12 100%	37 100%	49 100%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicities
Description	Dose limiting toxicity (DLT) was defined as any of the following occurring during the first cycle: Grade 4 thrombocytopenia, or grade 3 thrombocytopenia associated with bleeding, requirement for transfusion, febrile neutropenia, neutropenia with documented infection. Non-hematologic DLT included any other ≥ grade 3 non-hematologic toxicity that was clinically significant and considered by the investigator to be related to study drug. Alopecia and grade 3 allergic reaction/hypersensitivity with infusion were not considered DLTs.
Time Frame	Up to21 days

Outcome Measure Data

Analysis Population Description

At dose level 1, 2 and 3 three participants were treated with no dose limiting toxicities. Three additional participants were treated at dose level 3 with no dose limiting toxicities.

Arm/Group Title	Phase I: Dose Level 1	Phase I: Dose Level 2	Phase I: Dose Level 3
Arm/Group Description	A 3 + 3 dose escalation design was used to determine the maximum tolerated dose and the recommended phase II dose. Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 180 mg/m2 IV administration following pemetrexed on Day 1 of each cycle .	A 3 + 3 dose escalation design was used to determine the maximum tolerated dose and the recommended phase II dose. Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 220 mg/m2 IV administration following pemetrexed on Day 1 of each cycle .	A 3 + 3 dose escalation design was used to determine the maximum tolerated dose and the recommended phase II dose. Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 260 mg/m2 IV administration following pemetrexed on Day 1 of each cycle .
Measure Participants	3	3	6
Number [participants]	0 0%	0 0%	0 0%

2. Primary Outcome

Title	Number of Patients With Toxicities
Description	Toxicities was evaluated based on the standard NCI CTCAE Version 3.0 grading criteria. Attributable grade ≥ 3 hematologic and non-hematologic toxicities are presented here.
Time Frame	Up to 1 year

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase II: Pemetrexed and Abraxane
Arm/Group Description	Pemetrexed 500 mg/m2 plus Abraxane 260 mg/m2
Measure Participants	37
Count of Participants [Participants]	15 125%

3. Secondary Outcome

Title	Duration of Overall Survival
Description	From time of enrollment to the first observation of disease progression or death.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Of the 12 patients in the phase I component 10 were assessable for response. In the phase II component, 31 of 37 patients were evaluable for response.

Arm/Group Title	Phase I: Abraxane and Pemetrexed	Phase II: Abraxane and Pemetrexed
Arm/Group Description	A 3 + 3 dose escalation design was used to determine the maximum tolerated dose and the recommended phase II dose. Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 180 mg/m2, 220 mg/m2 and 260 mg/m2 IV administration following pemetrexed on Day 1 of each cycle .	Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 260 mg/m2IV administration following pemetrexed on Day 1 of each cycle
Measure Participants	10	31
Median (Standard Error) [months]	13.5 (0)	4.5 (0)

4. Secondary Outcome

Title	Number of Participants With Complete Response
Description	Per RECIST criteria, complete response (CR) is defined as the disappearance of all target lesions.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I: Abraxane and Pemetrexed	Phase II: Abraxane and Pemetrexed
Arm/Group Description	A 3 + 3 dose escalation design was used to determine the maximum tolerated dose and the recommended phase II dose. Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 180 mg/m2, 220 mg/m2 and 260 mg/m2 IV administration following pemetrexed on Day 1 of each cycle .	Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 260 mg/m2IV administration following pemetrexed on Day 1 of each cycle
Measure Participants	12	37
Number [participants]	0 0%	0 0%

5. Secondary Outcome

Title	Number of Participants With Stable Disease
Description	Stable Disease is measured from the start of the treatment until the criteria for disease progression are met. Progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0), as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I: Abraxane and Pemetrexed	Phase II: Abraxane and Pemetrexed
Arm/Group Description	A 3 + 3 dose escalation design was used to determine the maximum tolerated dose and the recommended phase II dose. Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 180 mg/m2, 220 mg/m2 and 260 mg/m2 IV administration following pemetrexed on Day 1 of each cycle .	Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 260 mg/m2IV administration following pemetrexed on Day 1 of each cycle
Measure Participants	12	37
Count of Participants [Participants]	7 58.3%	12 32.4%

6. Secondary Outcome

Title	Number of Participants With Partial Response
Description	At least a 30% decrease in the sum of the longest diameter of target lesions
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I: Abraxane and Pemetrexed	Phase II: Abraxane and Pemetrexed
Arm/Group Description	A 3 + 3 dose escalation design was used to determine the maximum tolerated dose and the recommended phase II dose. Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 180 mg/m2, 220 mg/m2 and 260 mg/m2 IV administration following pemetrexed on Day 1 of each cycle .	Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 260 mg/m2IV administration following pemetrexed on Day 1 of each cycle
Measure Participants	12	37
Count of Participants [Participants]	0 0%	5 13.5%

7. Secondary Outcome

Title	Number of Participants With Disease Control
Description	Disease control is complete response plus partial response plus stable disease from the start of treatment to death or disease progression.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Phase I: Abraxane and Pemetrexed	Phase II: Abraxane and Pemetrexed
Arm/Group Description	A 3 + 3 dose escalation design was used to determine the maximum tolerated dose and the recommended phase II dose. Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 180 mg/m2, 220 mg/m2 and 260 mg/m2 IV administration following pemetrexed on Day 1 of each cycle .	Alimta® (pemetrexed) 500 mg/m2 IV administration on Day 1 of each cycle with Abraxane® (ABI 007) 260 mg/m2IV administration following pemetrexed on Day 1 of each cycle
Measure Participants	12	37
Count of Participants [Participants]	7 58.3%	17 45.9%

Adverse Events

Time Frame	Up to 1 year
Adverse Event Reporting Description	Adverse events until they are resolved or stabilized, the patient is lost to follow-up, or the event is otherwise explained.
Arm/Group Title	Phase I: Abraxane and Alimta		Phase II: Abraxane and Alimta
Arm/Group Description	Three dose levels were tested. Pemetrexed 500mg/m2 day 1 and nab-paclitaxel day 1 at 180, 220, and 260 mg/m2 every 21 days. Abraxane: ABI-007 IV administration following pemetrexed on Day 1 of each cycle (infused over 30 minutes) Alimta: Pemetrexed IV administration on Day 1 of each cycle (infused over 10 minutes)		Pemetrexed 500mg/m2 day 1 and nab-paclitaxel day 1 at 260 mg/m2 every 21 days. Abraxane: ABI-007 IV administration following pemetrexed on Day 1 of each cycle (infused over 30 minutes) Alimta: Pemetrexed IV administration on Day 1 of each cycle (infused over 10 minutes)
All Cause Mortality
	Phase I: Abraxane and Alimta		Phase II: Abraxane and Alimta
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Phase I: Abraxane and Alimta		Phase II: Abraxane and Alimta
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)		6/37 (16.2%)
Blood and lymphatic system disorders
Neutropenia	0/12 (0%)		2/37 (5.4%)
Nasal Hemorrhage	0/12 (0%)		1/37 (2.7%)
Hemoglobin	0/12 (0%)		1/37 (2.7%)
Cardiac disorders
Cardiac Ischemia	0/12 (0%)		1/37 (2.7%)
Gastrointestinal disorders
Vomiting	0/12 (0%)		1/37 (2.7%)
General disorders
Fever	0/12 (0%)		1/37 (2.7%)
Infections and infestations
Skin Infection	0/12 (0%)		1/37 (2.7%)
Respiratory, thoracic and mediastinal disorders
Pneumonia	1/12 (8.3%)		0/37 (0%)
Other (Not Including Serious) Adverse Events
	Phase I: Abraxane and Alimta		Phase II: Abraxane and Alimta
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/12 (66.7%)		15/37 (40.5%)
Blood and lymphatic system disorders
Anemia	2/12 (16.7%)		2/37 (5.4%)
Leukopenia	1/12 (8.3%)		2/37 (5.4%)
Lymphopenia	0/12 (0%)		2/37 (5.4%)
Neutropenia	2/12 (16.7%)		3/37 (8.1%)
Hypoalbuminemia	1/12 (8.3%)		1/37 (2.7%)
Increased transaminases	0/12 (0%)		1/37 (2.7%)
Cardiac disorders
Cardiac Ischemia	0/12 (0%)		1/37 (2.7%)
Gastrointestinal disorders
Vomiting	0/12 (0%)		1/37 (2.7%)
General disorders
Fatigue	1/12 (8.3%)		0/37 (0%)
Hypersensitivity	0/12 (0%)		1/37 (2.7%)
Nervous system disorders
Sensory neuropathy	1/12 (8.3%)		0/37 (0%)
Skin and subcutaneous tissue disorders
Cellulitis	0/12 (0%)		1/37 (2.7%)

Limitations/Caveats

The phase II portion accrued 37 patients before early closure due to increasing the first-line pemetrexed/platinum doublet use in non-squamous NSCLC.

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.