Clinical Trial 20178

• Overview

  Study Title:

  An Open-Label Randomized Phase II Study of Combining Osimertinib with and without Ramucirumab in TKI-naïve EGFR-mutant Locally Advanced or Metastatic NSCLC

  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.

  Objective:

  Primary Objective: Determine whether, in patients with TKI-naïve locally advanced or metastatic EGFR mutant NSCLC the addition of ramucirumab to osimertinib improves progression free survival, compared to osimertinib alone Secondary Objectives: Determine whether osimertinib plus ramucirumab improves objective response rate (ORR) compared with osimertinib alone. Determine whether osimertinib plus ramucirumab improves overall survival (OS) compared with osimertinib alone. Determine whether osimertinib plus ramucirumab improves disease control rate (DCR) compared with osimertinib alone. Determine the safety and tolerability of combining osimertinib with ramucirumab compared with osimertinib alone.

• Treatments

  Therapies:

  Immunotherapy; Therapy (NOS)

  Medications:

  AZD9291 (Osimertinib); IMC-1121B (Ramucirumab); Osimertinib (); Ramucirumab ()

• Inclusion Criteria

  • 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.
  • Participants must have one of the following: NSCLC which harbors Epidermal Growth Factor Receptor (EGFR) Exon 19 deletion or 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.
  • Measurable disease
  • Participants 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
  • Participants must have adequate hematologic, coagulation, hepatic, and renal function per protocol
  • 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 Participant 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 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.
  • Females of childbearing potential and Non-sterilized males who are sexually active with a female partner of childbearing potential must agree to use adequate contraception for the duration of the study and 4 months after the last dose of study medication. If male Participants 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

  • Unable to stop medications that are potent inducers of CYP3A4 or known to prolong QT interval.
  • Any prior history of cancer within the past 2 years -some exceptions apply
  • Previous treatment with any EGFR TKIs
  • Previous treatment with any anti-Vascular Endothelial Growth Factor (VEGF) medications, including vandetinib, nintedanib, bevacizumab, or ramucirumab
  • 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 Participants 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 HIV. 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
  • Participants 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
  • History of hypersensitivity of osimertinib or ramucirumab
  • Mean resting corrected QT interval (QTc using Fridericia's formula) > 470 msec
  • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG eg, 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
  • Has experienced any arterial thromboembolic events
  • Has uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks)
  • Has experienced any Grade 3-4 GI bleeding within 3 months prior to first dose of protocol therapy
  • Has a history of DVT, pulmonary embolism, or any other significant thromboembolism, during the 3 months prior to first dose of protocol therapy
  • 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 within 2 months prior to first dose of protocol therapy
  • Has a prior history of GI perforation/fistula
  • Has a serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to first dose of protocol therapy
  • 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
  • Receiving chronic antiplatelet therapy. Once-daily aspirin use (maximum dose 325 mg/day) is permitted

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