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Study of Osimertinib With and Without Ramucirumab in Locally Advanced or Metastatic Non-Small Cell Lung Cancer (NSCLC)

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ClinicalTrials.gov Identifier: NCT03909334
Recruitment Status : Recruiting
First Posted : April 10, 2019
Last Update Posted : October 15, 2019
Sponsor:
Collaborators:
M.D. Anderson Cancer Center
Eli Lilly and Company
Information provided by (Responsible Party):
Xiuning Le, Hoosier Cancer Research Network

Brief Summary:
The primary objective of the study is to evaluate the efficacy of osimertinib plus ramucirumab versus osimertinib alone using progression free survival (PFS). Events associated with PFS include: disease progression per RECIST 1.1 and death due to any cause. A total of 150 patients will be enrolled and randomized in a 2:1 fashion (osimertinib plus ramucirumab vs. osimertinib) to the two treatment arms according to the following stratification factors: types of epidermal growth factor receptor (EGFR) mutations and presence of brain metastasis.

Condition or disease Intervention/treatment Phase
Non Small Cell Lung Cancer EGFR Gene Mutation Advanced Cancer Metastatic Cancer Drug: Osimertinib Drug: Ramucirumab Phase 2

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 150 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Open-Label Randomized Phase II Study of Combining Osimertinib With and Without Ramucirumab in Tyrosine Kinase Inhibitor (TKI)-naïve Epidermal Growth Factor Receptor (EGFR)-Mutant Locally Advanced or Metastatic NSCLC
Actual Study Start Date : July 25, 2019
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : June 2024

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Arm A (Osimertinib and Ramucirumab)
Osimertinib and Ramucirumab
Drug: Osimertinib
Osimertinib 80 mg orally on Day 1
Other Name: Tagrisso

Drug: Ramucirumab
Ramucirumab 10 mg/kg intravenously (IV) over 60 minutes on Day 1
Other Name: Cyramza

Active Comparator: Arm B (Osimertinib)
Osimertinib
Drug: Osimertinib
Osimertinib 80 mg orally on Day 1
Other Name: Tagrisso




Primary Outcome Measures :
  1. Progression Free Survival (PFS) [ Time Frame: 3 years ]
    Progression free survival (PFS) time will be calculated from the date of randomization to disease progression or death from any cause, whichever occurs the first.


Secondary Outcome Measures :
  1. Objective Response Rate (ORR) [ Time Frame: 1 year ]
    Objective Response Rate (ORR) is defined as the number (%) of subjects with measurable disease with at least one visit response of complete response (CR) or partial response (PR). Data obtained up until progression, or last evaluable assessment in the absence of progression, will be included in the assessment of ORR.

  2. Disease control rate (DCR) [ Time Frame: 2 years ]
    Disease control rate (DCR) is defined as the percentage of subjects who have a best overall response of CR or PR or stable disease (SD).

  3. Overall survival (OS) [ Time Frame: 3 years ]
    Overall survival (OS) time is defined from the date of randomization to death date. A patient is censored at the last follow-up date if death has not been observed.

  4. Assess frequency and severity of adverse events [ Time Frame: 2 years ]
    Toxicities will be measured in frequency and severity using CTCAE v5



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

Inclusion Criteria:

  • Written informed consent and HIPAA authorization for release of personal health information prior to registration. NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
  • Age ≥ 18 years at the time of consent.
  • Histologically or cytologically confirmed non-squamous, non-small cell lung cancer
  • Locally advanced or metastatic disease, not amenable to curative surgery or radiotherapy.
  • Patients must have one of the following:

    • NSCLC which harbors Epidermal Growth Factor Receptor (EGFR) Exon 19 deletion.
    • NSCLC which harbors EGFR L858R mutation. EGFR deletion/mutation must be documented by a Clinical Laboratory Improvement Amendments (CLIA) certified test (either from tissue or ctDNA from blood is allowed). If EGFR deletion/mutation testing has not been done, it should be ordered per standard of care.
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1 (Appendix A)
  • Measurable disease per RECIST 1.1
  • Patients with brain metastases are eligible if they are asymptomatic, are treated, or are neurologically stable for at least two weeks without the use of steroids or on stable or decreasing dose of ≤ 10 mg daily prednisone (or equivalent). These criteria must be met on day of consent.
  • Ability to take pills by mouth
  • Previous treatment with cytotoxic chemotherapy or immunotherapy is allowed
  • Patients must have adequate hematologic, coagulation, hepatic, and renal function. All laboratory tests must be obtained less than 4 weeks from study entry. This includes:

    • Absolute Neutrophil Count (ANC) >/= 1,500/mm3
    • platelet count >/=100,000/mm3
    • Hemoglobin (HgB) ≥ 9 g/dL (may be with transfusion)
    • Creatinine ≤ 1.5x ULN or creatinine clearance (measured via 24-hour urine collection) ≥40 mL/minute (that is, if serum creatinine is >1.5 times the ULN, a 24-hour urine collection to calculate creatinine clearance must be performed).
    • The patient's urinary protein is ≤ 1+ on dipstick or routine urinalysis (UA); if urine dipstick or routine analysis is ≥ 2+, a 24-hour urine collection for protein must demonstrate < 1000 mg of protein in 24 hours to allow participation in this protocol).
    • International Normalized Ratio (INR) ≤ 1.5 and a partial thromboplastin time (PTT) ≤ 5 seconds above the ULN (unless receiving anticoagulation therapy). Patients receiving warfarin must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy.
    • Total Serum Bilirubin ≤ 1.5 x ULN (Patients with known Gilbert Syndrome, a total bilirubin ≤ 3.0 x ULN, with direct bilirubin ≤ 1.5 x ULN)
    • Serum Glutamic Oxaloacetic Transaminase (SGOT), Serum Glutamic-Pyruvic Transaminase (SGPT) ≤ 3 X ULN if no liver metastasis present
    • SGOT, SGPT ≤ 5 X ULN if liver metastasis present
  • Females of childbearing potential must not be breast feeding and must have a negative serum pregnancy test within 7 days of starting of treatment. The patient must agree to use adequate contraception for a minimum of two weeks prior to receiving study medication until 3 months after discontinuation of the study medication. Acceptable methods of contraception are listed in Section 5.5. NOTE: Women will be considered post-menopausal if they have been amenorrheic for the past 12 months without an alternative medical cause. The following age-specific requirements must also apply: Women < 50 years old: they would be considered post-menopausal if they have been amenorrheic for the past 12 months or more following cessation of exogenous hormonal treatments. The levels of Luteinizing Hormone (LH) and Follicle-Stimulating Hormone (FSH) must also be in the post-menopausal range (as per the institution). Women ≥ 50 years old: they would be considered post-menopausal if they have been amenorrheic for the past 12 months or more following cessation of all exogenous hormonal treatments, or have had radiation-induced oophorectomy with the last menses > 1 year ago, or have had chemotherapy-induced menopause with >1 year interval since last menses, or have had surgical sterilization by either bilateral oophorectomy or hysterectomy.
  • Non-sterilized males who are sexually active with a female partner of childbearing potential must use adequate contraception for the duration of the study and 4 months after the last dose of study medication. If male patients wish to father children they should be advised to arrange for freezing of sperm samples prior to the start of the study medication.

Exclusion Criteria:

  • Previous treatment with any EGFR TKIs, including erlotinib, gefitinib, afatinib, avitinib, dacomitinib, rociletinib, or osimertinib.
  • Previous treatment with any anti-Vascular Endothelial Growth Factor (VEGF) medications, including vandetinib, nintedanib, bevacizumab, or ramucirumab.
  • Patients currently receiving (or unable to stop use prior to receiving the first dose of study treatment) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior). All patients must try to avoid concomitant use of any medications, herbal supplements and/or ingestion of foods with known inducer effects on CYP3A4.
  • Spinal cord compression unless asymptomatic or stable for at least 2 weeks prior to start of study treatment.
  • Any unresolved toxicities from prior therapy greater than CTCAE grade 1 (with the exception of alopecia grade 2) at the time of starting study treatment.
  • Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator's opinion makes it undesirable for the subject to participate in the trial or which would jeopardize compliance with the protocol, or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
  • Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product or previous significant bowel resection that would preclude adequate absorption of osimertinib.
  • Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease.
  • Patients with uncharacterized eye disorders.
  • Males and females of reproductive potential who are not using and effective method of birth control and females who are pregnant or breastfeeding or have a positive (urine or serum) pregnancy test prior to study entry.
  • History of hypersensitivity of osimertinib or ramucirumab (or active or inactive excipients of osimertinib or ramucirumab)
  • Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirement.
  • Any of the following cardiac criteria:

    • Mean resting corrected QT interval (QTc using Fridericia's formula) > 470 msec
    • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g., complete left bundle branch block, third degree heart block, second degree heart block, PR interval >250msec
    • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalemia, congenital long QT syndrome, family history of long QT syndrome or unexplained sudden death under 40 years of age in first degree relatives or any concomitant medication known to prolong the QT interval.
    • The patient has experienced any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to first dose of protocol therapy.
    • The patient has uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management.
  • The patient has experienced any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy.
  • The patient has a history of deep vein thrombosis (DVT), pulmonary embolism (PE), or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to first dose of protocol therapy.
  • The patient has cirrhosis at a level of Child-Pugh B (or worse) or cirrhosis (any degree) and a history of hepatic encephalopathy or clinically meaningful ascites resulting from cirrhosis. Clinically meaningful ascites is defined as ascites from cirrhosis requiring diuretics or paracentesis.
  • Any hemoptysis (defined as bright red blood or ≥ 1/2 teaspoon) within 2 months prior to first dose of protocol therapy or with radiographic evidence of intratumor cavitation or has radiologically documented evidence of major blood vessel invasion or encasement by cancer.
  • The patient has a prior history of GI perforation/fistula (within 6 months of first dose of protocol therapy) or risk factors for perforation.
  • The patient has a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy.
  • The patient has undergone major surgery within 28 days prior to first dose of protocol therapy, or minor surgery/subcutaneous venous access device placement within 7 days prior to the first dose of protocol therapy. The patient has elective or planned major surgery to be performed during the course of the clinical trial.
  • The patient is receiving chronic antiplatelet therapy, including aspirin, nonsteroidal anti-inflammatory drugs (NSAIDs, including ibuprofen, naproxen, and others), dipyridamole or clopidogrel, or similar agents. Once-daily aspirin use (maximum dose 325 mg/day) is permitted.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03909334


Contacts
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Contact: Xiuning Le, MD PhD 713-792-6363 dmusapatika@hoosiercancer.org
Contact: Lisa Benson 317-634-5842 ext 39 lbenson@hoosiercancer.org

Locations
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United States, Florida
Moffitt Cancer Center Recruiting
Tampa, Florida, United States, 33612
Contact: Marianna Castellano    813-745-2970    Marianna.CastellanoFornelli@moffitt.org   
Principal Investigator: Andreas Saltos, MD         
United States, Texas
MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Poulomi Bhattacharya       pbhattacharya@mdanderson.org   
Principal Investigator: Xiuning Le, MD         
Sponsors and Collaborators
Xiuning Le
M.D. Anderson Cancer Center
Eli Lilly and Company
Investigators
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Principal Investigator: Xiuning Le, MD PhD MD Anderson

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Responsible Party: Xiuning Le, Sponsor-Investigator, Hoosier Cancer Research Network
ClinicalTrials.gov Identifier: NCT03909334     History of Changes
Other Study ID Numbers: HCRN LUN18-335
First Posted: April 10, 2019    Key Record Dates
Last Update Posted: October 15, 2019
Last Verified: October 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No
Additional relevant MeSH terms:
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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
Ramucirumab
Osimertinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action