Randomized, Multi-center, Open-label, Study of PR104 Versus PR104/Docetaxel in Non-Small Cell Lung Cancer (NSCLC)

• Sponsor: Proacta, Incorporated (Industry)
• Overall Status: Terminated
• CT.gov ID: NCT00862134
• Collaborator: (none)
• Enrollment: 42
• Locations: 27
• Arms: 2
• Duration (Months): 14
• Patients Per Site: 1.6
• Patients Per Site Per Month: 0.1

Study Details

Study Description

Brief Summary

The current understanding of PR104 justifies the evaluation of PR104 with docetaxel in subjects with Non Small Cell Lung Cancer (NSCLC). These include:

• Aldo-keto reductase 1C3 (AKR1C3). NSCLC has been shown to express high levels of AKR1C3 in about one half of tumors tested. Subjects with high levels of AKR1C3 should have increased activation of PR104 within their tumor.

• Hypoxia. NSCLC has been demonstrated to be a tumor with hypoxia based on both direct tumor measurements (oxygen electrodes) and hypoxic positron emission tomography (PET) imaging. Tumor hypoxia in NSCLC should be sufficient to activate PR104 to its active metabolites PR104H and PR104M.

• Preclinical data. The use of docetaxel and PR104 alone and in combination in preclinical models demonstrates activity of PR104 as a single agent and supraadditive activity when PR104 and docetaxel are used in combination.

• Manageable toxicity. PR104 and docetaxel with Granulocyte Colony-stimulating Factor (G-CSF) have been combined in a prior phase I study. A Maximum Tolerated Dose (MTD) has been identified and the major toxicities of this combination are understood.

The current study will provide an estimate of the activity of PR104 in subjects with NSCLC. This information will prove valuable in defining the future clinical development of PR104, and in determining if PR104 has sufficient activity in NSCLC to warrant a larger phase III registration study in this indication.

Primary objectives

• Estimate the response rate (RR) of PR104/docetaxel

Secondary objectives

• Evaluate survival

• Evaluate progression free survival (PFS)

• Evaluate time to progression (TTP)

• Evaluate safety

• Evaluate the pharmacokinetics of PR104 and its metabolites

• Evaluate the pharmacokinetics of docetaxel

• Evaluate the tumor hypoxia using 18F-fluoromisonidazole (18F-MISO) PET imaging

• Collect diagnostic biopsy samples for the determination of AKR1C3

• Collect plasma samples for assessment of potential biomarkers of tumor hypoxia

Condition or Disease	Intervention/Treatment	Phase
Non-Small Cell Lung Cancer	Drug: PR104; Drug: docetaxel; Drug: docetaxel; Drug: Granulocyte colony-stimulating factor	Phase 2

Detailed Description

A randomized phase II, multi-center, open-label, study of docetaxel versus docetaxel/PR104.

Following informed consent, subjects will undergo baseline evaluation with history, physical exams, blood work and disease assessment. Selected subjects will undergo PET imaging with F18 fluoromisonidazole (F18-FMISO) and Fludeoxyglucose (FDG) for assessment of hypoxia and glucose metabolism, and pharmacokinetics of PR104.

Subjects will be randomized between arm 1 consisting of docetaxel, 75 mg/m^{2, administered intravenously (IV), every 21 days (an approved dose and schedule) and arm 2 consisting of docetaxel, 60 mg/m}2 with PR104 at 770 mg/m^2, IV, every 21 days. Subjects randomized to PR104/docetaxel will receive prophylactic G-CSF. One cycle will be 21 days in duration. Subjects will be evaluated weekly. A disease assessment will be performed every six weeks. Subjects with progression will be removed from study. Subjects with a response or stable disease may continue on study if this is considered beneficial by their physician.

Study Design

• Study Type: Interventional
• Actual Enrollment: 42 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Phase II, Multi-Center, Open-Label Trial of PR104 and Docetaxel in Patients With Advanced Non-Small Cell Lung Cancer
• Study Start Date: Mar 1, 2009
• Actual Primary Completion Date: Jan 1, 2010
• Actual Study Completion Date: May 1, 2010

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Docetaxel 75 mg/m^2 Subjects randomized to the docetaxel arm will be administered 75 mg/m^2, IV, every 21 days (an approved dose and schedule)	Drug: docetaxel; 75 mg/m^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops.; Other Names: Taxotere
Experimental: PR104 + 60 mg/m^2 docetaxel Subjects randomized to the PR104/docetaxel arm will be administered 60 mg/m^2 docetaxel, IV, every 21 days plus 770 mg/m^2 PR104, IV, every 21 days and prophylactic G-CSF.	Drug: PR104; 770 mg/m^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops.; Drug: docetaxel; 60 mg/m^2, IV, every 21 days. Number of Cycles: until progression or unacceptable toxicity develops.; Other Names: Taxotere ; Drug: Granulocyte colony-stimulating factor; Subjects randomized to PR104/docetaxel will receive prophylactic G-CSF per package insert administration recommendations. Number of Cycles: until progression or unacceptable toxicity develops.; Other Names: G-CSF GCSF

Outcome Measures

Primary Outcome Measures

1. Number of Participants That Achieved a Response (Complete or Partial) After Receiving PR104/Docetaxel Versus Docetaxel Alone [Participants were followed for the duration on study, an average of 4 months]

   Defined as the number of subjects with complete response (CR) or partial response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria

Secondary Outcome Measures

1. Safety and Tolerability: Serious Adverse Events [30 days following last administration of study treatment]

   The number of participants with at least one Serious Adverse Event was measured.

2. Positive Aldo-keto Reductase 1C3 (AKR1C3) Expression in Participating Patients [Within 1 year of enrollment]

   AKR1C3 was evaluated on a semi-quantitative scale, and the percentage of cells staining at each of the following four levels was recorded: 0 (unstained), 1+ (weak staining), 2+ (moderate staining) and 3+ (strong staining). Patients with a strong staining score (3+) were considered to be AKR1C3 positive

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Subjects with locally advanced or metastatic NSCLC (stage IIIb/IV) who have relapsed following adjuvant or first line therapy with a platinum containing regimen, and are appropriate candidates for treatment with single agent docetaxel

• Confirmed NSCLC by prior pathological analysis (tissue aspirate or biopsy)

• At least 21 days from prior chemotherapy

• At least 30 days from prior irradiation therapy

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• Life expectancy of 12 weeks or more

• Adequate hematologic function [Absolute neutrophil count (ANC) ≥ 1.5 x 10^{9/L; platelet count ≥100x10}9/L; hemoglobin ≥8.5 g /dL maintained in the absence of red blood cell transfusions; and prothrombin time international normalized ratio ≤1.7; or prothrombin time ≤2 seconds above control)

• Adequate hepatic function (albumin ≥2.8 g/dL; total bilirubin ≤2 mg/dL [51.3 μmol/L]; and alanine aminotransferase and aspartate aminotransferase ≤1.5 times the upper limit of the normal range)

• Adequate renal function (serum creatinine ≤2.0 times the upper limit of the normal range or creatinine clearance ≥60 mL/min).

• At least one untreated target lesion that could be measured in one dimension, according to the Response Evaluation Criteria in Solid Tumors (RECIST)

Exclusion Criteria:

• Previous treatment with docetaxel (prior treatment with paclitaxel permitted)

• Receipt of more than one prior systemic chemotherapy regimen

• Active concomitant malignancy likely to effect any of the primary or secondary outcome measures in the current study

• Women who are pregnant, breast-feeding or planning to become pregnant during the study

• Men or women of reproductive-potential who are unwilling to use an effective method of contraception during the study and for 30 days following the last dose

• Evidence of a significant medical disorder or laboratory finding that, in the opinion of the Investigator, compromises the subject's safety during study participation

• Active Central Nervous System (CNS) metastatic disease requiring intervention

• Less than 4 weeks since major surgery

• Known human immunodeficiency virus (HIV) positivity

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Sharp Clinical Oncology Research	San Diego	California	United States	92123
2	University of Miami/Sylvester Comprehensive Cancer Center	Miami	Florida	United States	33136
3	Northwestern University	Chicago	Illinois	United States	60611
4	Orchard Research, LLC	Skokie	Illinois	United States	60076
5	Midwestern Regional Medical Center	Zion	Illinois	United States	60099
6	St. Francis Health Services	Beech Grove	Indiana	United States	46107
7	McFarland Clinic/William R. Bliss Cancer Center	Ames	Iowa	United States	50010
8	Iowa Blood & Cancer Care	Cedar Rapids	Iowa	United States	52402
9	Cancer Center of Kansas	Wichita	Kansas	United States	67214
10	Montgomery Cancer Center	Mt. Sterling	Kentucky	United States	40353
11	Baton Rouge General/Penington	Baton Rouge	Louisiana	United States	70809
12	Annapolis Oncology Center	Annapolis	Maryland	United States	21401
13	Lapidus Cancer Center/Sinai Hospital	Baltimore	Maryland	United States	21215
14	Kalamazoo Hematology & Oncology	Kalamazoo	Michigan	United States	49048
15	VA Sierra Nevada Health Care System	Reno	Nevada	United States	89502
16	VA Medical Center	Durham	North Carolina	United States
17	Piedmont Hematology Oncology Associates, PLLC	Winston-Salem	North Carolina	United States	27103
18	Cincinnati VA Medical Center	Cincinnati	Ohio	United States	45220
19	University of Pennsylvania	Philadelphia	Pennsylvania	United States
20	WJB Dorn VA Medical Center	Columbia	South Carolina	United States	29209
21	ACORN	Memphis	Tennessee	United States	38120
22	Mary Crowley Medical Research Center	Dallas	Texas	United States	75246
23	The Center for Cancer and Blood Disorders	Fort Worth	Texas	United States	76104
24	Texas Oncology - Allison Cancer Center	Midland	Texas	United States	79701
25	Scott & White Memorial Hospital	Temple	Texas	United States	76508
26	McGill University	Montreal	Quebec	Canada	H2W 1S6
27	Waikato District Health Board	Hamilton		New Zealand

Sponsors and Collaborators

• Proacta, Incorporated

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Proacta, Incorporated
• ClinicalTrials.gov Identifier: NCT00862134
• Other Study ID Numbers: PR104-2003; NCT00840021
• First Posted: Mar 16, 2009
• Last Update Posted: Jan 10, 2013
• Last Verified: Jan 1, 2013

• Additional relevant MeSH terms: Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Docetaxel; Lenograstim

Study Results

Participant Flow

Arm/Group Title	Docetaxel	PR104 + Docetaxel
Arm/Group Description	75 mg/m^2 docetaxel, IV, every 21 days	Subjects randomized to the PR104/docetaxel arm will be administered 60 mg/m^2 docetaxel, IV, every 21 days plus 770 mg/m^2 PR104, IV, every 21 days and prophylactic Granulocyte Colony-stimulating Factor (G-CSF).
Period Title: Overall Study
STARTED	19	23
COMPLETED	8	11
NOT COMPLETED	11	12

Baseline Characteristics

Arm/Group Title	Docetaxel	PR104 + Docetaxel	Total
Arm/Group Description	75 mg/m^2 docetaxel, IV, every 21 days	Subjects randomized to the PR104/docetaxel arm will be administered 60 mg/m^2 docetaxel, IV, every 21 days plus 770 mg/m^2 PR104, IV, every 21 days and prophylactic G-CSF.	Total of all reporting groups
Overall Participants	19	23	42
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	14 73.7%	9 39.1%	23 54.8%
>=65 years	5 26.3%	14 60.9%	19 45.2%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	61 (7.78)	64 (7.58)	63 (7.70)
Sex: Female, Male (Count of Participants)
Female	7 36.8%	8 34.8%	15 35.7%
Male	12 63.2%	15 65.2%	27 64.3%
Region of Enrollment (participants) [Number]
United States	19 100%	20 87%	39 92.9%
Canada	0 0%	3 13%	3 7.1%

Outcome Measures

1. Primary Outcome

Title	Number of Participants That Achieved a Response (Complete or Partial) After Receiving PR104/Docetaxel Versus Docetaxel Alone
Description	Defined as the number of subjects with complete response (CR) or partial response (PR) using Response Evaluation Criteria in Solid Tumors (RECIST) criteria
Time Frame	Participants were followed for the duration on study, an average of 4 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Docetaxel	PR104 + Docetaxel
Arm/Group Description	75 mg/m^2 docetaxel, IV, every 21 days	Subjects randomized to the PR104/docetaxel arm will be administered 60 mg/m^2 docetaxel, IV, every 21 days plus 770 mg/m^2 PR104, IV, every 21 days and prophylactic G-CSF.
Measure Participants	17	21
Complete Response (CR)	0 0%	0 0%
Partial Response (PR)	1 5.3%	3 13%

2. Secondary Outcome

Title	Safety and Tolerability: Serious Adverse Events
Description	The number of participants with at least one Serious Adverse Event was measured.
Time Frame	30 days following last administration of study treatment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Docetaxel	PR104 + Docetaxel
Arm/Group Description	75 mg/m^2 docetaxel, IV, every 21 days	Subjects randomized to the PR104/docetaxel arm will be administered 60 mg/m^2 docetaxel, IV, every 21 days plus 770 mg/m^2 PR104, IV, every 21 days and prophylactic G-CSF.
Measure Participants	17	23
Number [participants]	8 42.1%	5 21.7%

3. Secondary Outcome

Title	Positive Aldo-keto Reductase 1C3 (AKR1C3) Expression in Participating Patients
Description	AKR1C3 was evaluated on a semi-quantitative scale, and the percentage of cells staining at each of the following four levels was recorded: 0 (unstained), 1+ (weak staining), 2+ (moderate staining) and 3+ (strong staining). Patients with a strong staining score (3+) were considered to be AKR1C3 positive
Time Frame	Within 1 year of enrollment

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Docetaxel	PR104 + Docetaxel
Arm/Group Description	75 mg/m^2 docetaxel, IV, every 21 days	Subjects randomized to the PR104/docetaxel arm will be administered 60 mg/m^2 docetaxel, IV, every 21 days plus 770 mg/m^2 PR104, IV, every 21 days and prophylactic G-CSF.
Measure Participants	11	12
Number [participants]	5 26.3%	8 34.8%

Adverse Events

Arm/Group Title	Docetaxel		PR104 + Docetaxel
Arm/Group Description	75 mg/m^2 docetaxel, IV, every 21 days		Subjects randomized to the PR104/docetaxel arm will be administered 60 mg/m^2 docetaxel, IV, every 21 days plus 770 mg/m^2 PR104, IV, every 21 days and prophylactic G-CSF.
All Cause Mortality
	Docetaxel		PR104 + Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Docetaxel		PR104 + Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/17 (47.1%)		5/23 (21.7%)
Blood and lymphatic system disorders
Neutropenic Fever	1/17 (5.9%)		1/23 (4.3%)
Cardiac disorders
Acute Myocardial Infarction	0/17 (0%)		0/23 (0%)
Gastrointestinal disorders
Ileus, GI	0/17 (0%)		0/23 (0%)
Gastrointestinal Bleed	0/17 (0%)		1/23 (4.3%)
Gastroenteritis	1/17 (5.9%)		1/23 (4.3%)
General disorders
Chest Pain (atypical)	2/17 (11.8%)		0/23 (0%)
Infections and infestations
Sepsis	1/17 (5.9%)		0/23 (0%)
Acute RLL Pneumonia	2/17 (11.8%)		0/23 (0%)
Neutropenic Sepsis	0/17 (0%)		1/23 (4.3%)
Injury, poisoning and procedural complications
Spinal Cord Compression	0/17 (0%)		1/23 (4.3%)
Metabolism and nutrition disorders
Dehydration	1/17 (5.9%)		2/23 (8.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	1/17 (5.9%)		0/23 (0%)
Acute Respiratory Distress	1/17 (5.9%)		0/23 (0%)
Other (Not Including Serious) Adverse Events
	Docetaxel		PR104 + Docetaxel
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	17/17 (100%)		23/23 (100%)
Blood and lymphatic system disorders
Anaemia	10/17 (58.8%)		14/23 (60.9%)
Neutropenia	10/17 (58.8%)		14/23 (60.9%)
Leukopenia	10/17 (58.8%)		13/23 (56.5%)
Thrombocytopenia	0/17 (0%)		7/23 (30.4%)
Cardiac disorders
Acute myocardial infarction	1/17 (5.9%)		0/23 (0%)
Angina pectoris	1/17 (5.9%)		0/23 (0%)
Gastrointestinal disorders
Constipation	3/17 (17.6%)		1/23 (4.3%)
Diarrhoea	1/17 (5.9%)		2/23 (8.7%)
Dyspepsia	1/17 (5.9%)		1/23 (4.3%)
Nausea	2/17 (11.8%)		0/23 (0%)
Stomatitis	1/17 (5.9%)		1/23 (4.3%)
Vomiting	2/17 (11.8%)		0/23 (0%)
Abdominal pain	1/17 (5.9%)		0/23 (0%)
Gastric ileus	1/17 (5.9%)		0/23 (0%)
Glossodynia	1/17 (5.9%)		0/23 (0%)
General disorders
Fatigue	9/17 (52.9%)		8/23 (34.8%)
Non-cardiac chest pain	2/17 (11.8%)		2/23 (8.7%)
Asthenia	1/17 (5.9%)		0/23 (0%)
Irritability	1/17 (5.9%)		0/23 (0%)
Oedema	1/17 (5.9%)		0/23 (0%)
Oedema peripheral	1/17 (5.9%)		0/23 (0%)
Diarrhoea	1/17 (5.9%)		2/23 (8.7%)
Hepatobiliary disorders
Hyperbilirubinaemia	1/17 (5.9%)		0/23 (0%)
Infections and infestations
Pneumonia	5/17 (29.4%)		0/23 (0%)
Candidiasis	1/17 (5.9%)		1/23 (4.3%)
Bronchitis	1/17 (5.9%)		0/23 (0%)
Fungal infection	1/17 (5.9%)		0/23 (0%)
Nasopharyngitis	1/17 (5.9%)		0/23 (0%)
Staphylococcal infection	1/17 (5.9%)		0/23 (0%)
Urinary tract infection	1/17 (5.9%)		0/23 (0%)
Viral infection	1/17 (5.9%)		0/23 (0%)
Injury, poisoning and procedural complications
Clavicle fracture	1/17 (5.9%)		0/23 (0%)
Investigations
Alanine aminotransferase increased	1/17 (5.9%)		1/23 (4.3%)
Aspartate aminotransferase increased	1/17 (5.9%)		0/23 (0%)
Electrocardiogram abnormal	1/17 (5.9%)		0/23 (0%)
Hepatitis C virus	1/17 (5.9%)		0/23 (0%)
Metabolism and nutrition disorders
Hyperglycaemia	8/17 (47.1%)		7/23 (30.4%)
Hypoalbuminaemia	6/17 (35.3%)		4/23 (17.4%)
Dehydration	2/17 (11.8%)		2/23 (8.7%)
Hyponatraemia	0/17 (0%)		3/23 (13%)
Anorexia	2/17 (11.8%)		1/23 (4.3%)
Hypocalcaemia	2/17 (11.8%)		1/23 (4.3%)
Hypokalaemia	1/17 (5.9%)		1/23 (4.3%)
Musculoskeletal and connective tissue disorders
Back pain	1/17 (5.9%)		2/23 (8.7%)
Myalgia	3/17 (17.6%)		0/23 (0%)
Arthralgia	1/17 (5.9%)		1/23 (4.3%)
Nervous system disorders
Headache	3/17 (17.6%)		0/23 (0%)
Dizziness	1/17 (5.9%)		0/23 (0%)
Psychiatric disorders
Insomnia	3/17 (17.6%)		1/23 (4.3%)
Delirium	1/17 (5.9%)		0/23 (0%)
Reproductive system and breast disorders
Benign prostatic hyperplasia	1/17 (5.9%)		0/23 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	2/17 (11.8%)		4/23 (17.4%)
Cough	1/17 (5.9%)		2/23 (8.7%)
Hypoxia	1/17 (5.9%)		1/23 (4.3%)
Respiratory distress	2/17 (11.8%)		0/23 (0%)
Chronic obstructive pulmonary disease	1/17 (5.9%)		0/23 (0%)
Epistaxis	1/17 (5.9%)		0/23 (0%)
Pleural effusion	1/17 (5.9%)		0/23 (0%)
Pulmonary embolism	1/17 (5.9%)		0/23 (0%)
Pulmonary hypertension	1/17 (5.9%)		0/23 (0%)
Skin and subcutaneous tissue disorders
Alopecia	2/17 (11.8%)		2/23 (8.7%)
Rash	1/17 (5.9%)		1/23 (4.3%)
Decubitus ulcer	1/17 (5.9%)		0/23 (0%)
Skin exfoliation	1/17 (5.9%)		0/23 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Single site data may be published/presented prior to the publication of multi-center data from overall study if agreed to by the sponsor in writing, or 12 months have elapsed following termination or completion of the study, whichever comes first.