Phase II Trial of Carboplatin and Pemetrexed +/- OGX-427 in Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer (Spruce)

• ClinicalTrials.gov Identifier: NCT01829113
• Recruitment Status: Completed
• First Posted: April 11, 2013
• Results First Posted: June 8, 2018
• Last Update Posted: June 8, 2018
• Sponsor: SCRI Development Innovations, LLC
• Collaborator: Achieve Life Sciences
• Information provided by (Responsible Party): SCRI Development Innovations, LLC

Study Description

Brief Summary:

This randomized phase II study will compare the efficacy and safety of the combination of carboplatin and pemetrexed with and without OGX-427 in patients with previously untreated advanced non-squamous NSCLC.

Condition or disease	Intervention/treatment	Phase
Non Squamous Non Small Cell Lung Cancer	Drug: OGX-427; Drug: Placebo	Phase 2

Detailed Description:

Modern doublet chemotherapy improves survival in patients with advanced non-small cell lung cancer (NSCLC) compared with supportive care alone, with non-squamous NSCLC patients treated with platinum/pemetrexed living longer than patients treated with platinum/gemcitabine. Despite these advances, poor outcomes with advanced disease warrant exploration of novel drugs with unique mechanisms of action. Preclinical evidence in lung cancer models shows promising antitumor activity with OGX-427 in combination with platinum based therapy or pemetrexed. In this double-blind, placebo-controlled, Phase II study, pemetrexed and carboplatin plus OGX-427 followed by maintenance pemetrexed and OGX-427 will be compared with pemetrexed and carboplatin plus placebo followed by maintenance pemetrexed and placebo in patients with previously untreated advanced non-squamous NSCLC.

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 155 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Double-Blind Randomized Phase II Trial of Carboplatin and Pemetrexed With or Without OGX-427 in Patients With Previously Untreated Stage IV Non-Squamous-Non-Small-Cell Lung Cancer (The Spruce Clinical Trial)
• Actual Study Start Date: July 2013
• Actual Primary Completion Date: April 19, 2017
• Actual Study Completion Date: April 19, 2017

Arms and Interventions

Arm	Intervention/treatment
Experimental: OGX-427; Three loading doses of OGX-427 at 600mg intravenously (IV) will be administered over 9 days. Following the loading dose period, OGX-427 will be administered at 600mg IV weekly Days 1, 8 and 15 of each 21 day cycle during the Treatment Phase. The Treatment Phase will be followed by a Maintenance Phase of OGX-427 administered at 600mg IV weekly Days 1, 8 and 15 of each 21 day cycle.	Drug: OGX-427; Three loading doses of 600mg OGX-427 will be administered intravenously (IV) during a 9 day period. Then 600mg IV OGX-427 will be given weekly on Days 1, 8 and 15 of each 21 day cycle prior to the administration of pemetrexed (500mg/m^2 IV) and carboplatin (AUC 6 IV) on Day 1 of each cycle for a maximum of four treatment cycles. Patients who respond to treatment or have stable disease will continue to receive 600 mg IV OGX-427 plus 500mg/m2 IV pemetrexed weekly until toxicity or disease progression.; Other Name: apatorsen
Placebo Comparator: Placebo; Three loading doses of placebo will be administered intravenously (IV) over 9 days. Following the loading dose period, placebo will be administered IV weekly Days 1, 8 and 15 of each 21 day cycle during the Treatment Phase. The Treatment Phase will be followed by a Maintenance Phase of placebo administered IV weekly Days 1, 8 and 15 of each 21 day cycle.	Drug: Placebo; Three loading doses of placebo will be administered intravenously (IV) during a 9 day period. Then placebo (IV) will be given weekly on Days 1, 8 and 15 of each 21 day cycle prior to the administration of pemetrexed (500mg/m^2 IV) and carboplatin (AUC 6 IV) on Day 1 of each cycle for a maximum of four treatment cycles. Patients who respond to treatment or have stable disease will continue to receive placebo (IV) plus 500mg/m2 IV pemetrexed weekly until toxicity or disease progression.

Outcome Measures

Primary Outcome Measures :

1. Median Progression-Free Survival [ Time Frame: Every 6 weeks for up to 24 months ]
   Defined as the time (in months) from date of randomization to the date of first observation of progression based on radiological assessment by Response Evaluation Criteria in Solid Tumors (RECIST) v 1.1, or date of death from any cause, in the absence of progressive disease (PD) or censored at the date of last adequate tumor assessment. Progressive Disease is defined by RECIST v1.1 as at least a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest (nadir) sum while on study (this includes the baseline sum if that is the smallest on study), or the appearance of one or more new lesions.

Secondary Outcome Measures :

1. Number of OGX-427 Versus Placebo Participants With an Objective Response [ Time Frame: Every 6 weeks for up to 24 months ]
   Defined as the number of patients with objective evidence of complete or partial response (CR or PR) using RECIST v 1.1. A CR is the complete disappearance of all target lesions. A PR is a decrease in baseline of 30% or more of the diameter(s) of all target lesions.
2. Median Overall Survival [ Time Frame: Every 6 weeks for up to 41 months ]
   Defined as the time (in months) from date of randomization to date of death from any cause, or censored at the date last known alive.
3. Number of Patients With a Treatment-Related Adverse Event as a Measure of Safety. [ Time Frame: Weekly during each 21 days cycle and for 30 days after last dose for up to 29 Months ]
   A treatment-related adverse event was any untoward medical occurrence in a participant which was considered to have a relationship with the study drug (suspected to be possibly or probably related to the study drug per the Investigator's assessment). Adverse events were evaluated using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03.

Eligibility Criteria

• Ages Eligible for Study: 18 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Criteria

Inclusion Criteria:

1. Histologic or cytologic diagnosis of advanced NSCLC, excluding squamous cell and small cell histology. Tumors with mixed NSCLC histologies are eligible, as long as the predominant histology is not squamous. If small-cell elements are present or not otherwise specified histologically, the patient is not eligible.
2. Metastatic disease (according to American Joint Committee on Cancer (AJCC) staging system, v7.0).
3. No prior systemic chemotherapy, immunotherapy, targeted therapy, or biological therapy for metastatic disease; previous adjuvant or neoadjuvant therapy for Stage I, II, or III disease is allowed as long as the interval from the end of treatment until disease progression was >12 months.
4. No prior radiation therapy to the whole pelvis or to ≥25% of the total bone marrow area. Other radiation therapy must be completed at least 2 weeks prior to study entry. Must have recovered from acute adverse effects prior to study entry.
5. At least one measurable lesion according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1.
6. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.

7. Baseline laboratory values as follows:

   • Absolute neutrophil count (ANC) ≥1500/μL
   • Hemoglobin (Hgb) ≥10 g/dL
   • Platelets ≥100,000/μL
   • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST), ≤3.0 x the upper limit of normal (ULN); 5 x ULN if known hepatic metastases.
   • Total bilirubin ≤1.5 x ULN, unless secondary to Gilbert's disease
   • Serum creatinine ≤1.5 x ULN. If creatinine is >1.5, calculate creatinine clearance (CrCl) ≥45 mL/min by the Cockcroft-Gault method:

   Glomerular Filtration Rate (GFR) = (140-age) x (weight/kg) x (0.85 if female)/(72 x serum creatinine mg/dL)

8. Fertile male patients willing to use adequate contraceptive measures.
9. Female patients who are not of child-bearing potential, and fertile female patients of child-bearing potential who agree to use adequate contraceptive measures, who are not breastfeeding, and who have a negative serum or urine pregnancy test within 72 hours prior to start of randomization.
10. Life expectancy ≥ 12 weeks.
11. Must be ≥18 years of age at the time of consent.
12. Willingness and ability to comply with trial and follow-up procedures.
13. Ability to understand the nature of this trial and give written informed consent.

Exclusion Criteria:

1. Known anaplastic lymphoma kinase (ALK) translocation and epidermal growth factor receptor (EGFR) "activating" mutations where first-line treatment with targeted tyrosine kinase inhibitor therapy is more appropriate.
2. Known central nervous system (CNS) disease other than neurologically stable, treated brain metastases defined as metastasis having no evidence of progression or hemorrhage after treatment and no ongoing requirements for corticosteroids, (e.g., dexamethasone) for at least 2 weeks.

3. Any of the following cardiac diseases currently or within the last 6 months as defined by New York Heart Association (NYHA) ≥ Class 2:

   • Unstable angina pectoris
   • Congestive heart failure
   • Acute myocardial infarction
   • Conduction abnormality not controlled with pacemaker or medication
   • Significant ventricular or supraventricular arrhythmias (Patients with chronic rate-controlled atrial fibrillation in the absence of other cardiac abnormalities are eligible).
4. Patients currently receiving therapeutic anticoagulation.
5. Pregnant or lactating women.
6. Any serious, active underlying medical condition that would impair the ability of the patient to receive study treatment, such as diabetes mellitus or infection.
7. Unable or unwilling to take folic acid or vitamin B12.
8. Active second malignancy (except non-melanomatous skin or superficial bladder cancer) defined as requiring current need for cancer therapy or at high risk of recurrence (>30%) during the study.
9. Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol.
10. Inability or unwillingness to comply with trial and/or follow-up procedures outlined in the protocol.

Contacts and Locations

Locations

United States, Colorado

Rocky Mountain Cancer Center

Denver, Colorado, United States, 80218

United States, Florida

Florida Cancer Specialists-South

Fort Myers, Florida, United States, 33916

Florida Hospital Cancer Insitute

Orlando, Florida, United States, 32804

Florida Cancer Specialists-North

Saint Petersburg, Florida, United States, 33705

United States, Kentucky

Baptist Hospital East

Louisville, Kentucky, United States, 40207

United States, Maryland

Center for Cancer and Blood Disorders

Bethesda, Maryland, United States, 20817

United States, Missouri

Research Medical Center

Kansas City, Missouri, United States, 64132

United States, Nebraska

Nebraska Methodist Hospital

Omaha, Nebraska, United States, 68114

United States, New Jersey

Hematology-Oncology Associates of Northern NJ

Morristown, New Jersey, United States, 07932

United States, Ohio

Oncology Hematology Care, Inc.

Cincinnati, Ohio, United States, 45242

United States, South Carolina

South Carolina Oncology Associates

Columbia, South Carolina, United States, 29210

United States, Tennessee

Tennessee Oncology - Chattanooga

Chattanooga, Tennessee, United States, 37404

Tennessee Oncology

Nashville, Tennessee, United States, 37203

United States, Texas

The Center for Cancer and Blood Disorders

Fort Worth, Texas, United States, 76104

United States, Virginia

Peninsula Cancer Institute

Newport News, Virginia, United States, 23601

Virginia Cancer Institute

Richmond, Virginia, United States, 23230

Sponsors and Collaborators

SCRI Development Innovations, LLC

Achieve Life Sciences

Investigators

• Study Chair: David R. Spigel, M.D.; SCRI

  Study Documents (Full-Text)

Documents provided by SCRI Development Innovations, LLC:

Study Protocol  [PDF] November 5, 2014

Statistical Analysis Plan  [PDF] May 21, 2015

More Information

Publications:

Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, Dancey J, Arbuck S, Gwyther S, Mooney M, Rubinstein L, Shankar L, Dodd L, Kaplan R, Lacombe D, Verweij J. New response evaluation criteria in solid tumours: revised RECIST guideline (version 1.1). Eur J Cancer. 2009 Jan;45(2):228-47. doi: 10.1016/j.ejca.2008.10.026.

Grønberg BH, Bremnes RM, Fløtten O, Amundsen T, Brunsvig PF, Hjelde HH, Kaasa S, von Plessen C, Stornes F, Tollåli T, Wammer F, Aasebø U, Sundstrøm S. Phase III study by the Norwegian lung cancer study group: pemetrexed plus carboplatin compared with gemcitabine plus carboplatin as first-line chemotherapy in advanced non-small-cell lung cancer. J Clin Oncol. 2009 Jul 1;27(19):3217-24. doi: 10.1200/JCO.2008.20.9114. Epub 2009 May 11.

Scagliotti GV, Parikh P, von Pawel J, Biesma B, Vansteenkiste J, Manegold C, Serwatowski P, Gatzemeier U, Digumarti R, Zukin M, Lee JS, Mellemgaard A, Park K, Patil S, Rolski J, Goksel T, de Marinis F, Simms L, Sugarman KP, Gandara D. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol. 2008 Jul 20;26(21):3543-51. doi: 10.1200/JCO.2007.15.0375. Epub 2008 May 27.

Vogelzang NJ, Rusthoven JJ, Symanowski J, Denham C, Kaukel E, Ruffie P, Gatzemeier U, Boyer M, Emri S, Manegold C, Niyikiza C, Paoletti P. Phase III study of pemetrexed in combination with cisplatin versus cisplatin alone in patients with malignant pleural mesothelioma. J Clin Oncol. 2003 Jul 15;21(14):2636-44.

Wu R, Kausar H, Johnson P, Montoya-Durango DE, Merchant M, Rane MJ. Hsp27 regulates Akt activation and polymorphonuclear leukocyte apoptosis by scaffolding MK2 to Akt signal complex. J Biol Chem. 2007 Jul 27;282(30):21598-608. Epub 2007 May 17.

Zheng C, Lin Z, Zhao ZJ, Yang Y, Niu H, Shen X. MAPK-activated protein kinase-2 (MK2)-mediated formation and phosphorylation-regulated dissociation of the signal complex consisting of p38, MK2, Akt, and Hsp27. J Biol Chem. 2006 Dec 1;281(48):37215-26. Epub 2006 Oct 2.

• Responsible Party: SCRI Development Innovations, LLC
• ClinicalTrials.gov Identifier: NCT01829113
• Other Study ID Numbers: SCRI LUN 229
• First Posted: April 11, 2013
• Results First Posted: June 8, 2018
• Last Update Posted: June 8, 2018
• Last Verified: June 2018

Keywords provided by SCRI Development Innovations, LLC:

Recurrent Lung Cancer; Stage IV Lung Cancer; OGX-427; Sarah Cannon Research Institute; SCRI; OncoGenex; NSCLC; Non Small Cell Lung Cancer

Additional relevant MeSH terms:

Lung Neoplasms; Carcinoma, Non-Small-Cell Lung; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases; Carcinoma, Bronchogenic; Bronchial Neoplasms