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Carcinoma, Non-Small-Cell LungPhase 2NCT03904108

Platinum-Based Chemotherapy Plus Ramucirumab in Patients With Advanced NSCLC Who Have Progressed on First Line Anti-PD-1 Immunotherapy

A Phase 2 study testing Ramucirumab in people with Carcinoma, Non-Small-Cell Lung, run by ROGER S KERESZTES MD at 1 site in United States.

Terminated

Stopped early. The study ended before it was planned to and will not resume.

Official record
Search all trials

Trial summary

This is a non-randomized, phase-II study of platinum doublet chemotherapy plus ramucirumab in patients with advanced NSCLC who have progressed on first line anti-PD-1 Immunotherapy. Up to 25 evaluable participants will be enrolled over a period of 2 years. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Carcinoma, Non-Small-Cell Lung
What is being tested?
Ramucirumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
3 participants
Where
1 siteUnited States
Study dates
27 Jun 2019to 27 Jul 2020
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Histologically confirmed stage IV NSCLC per 8th IASCL (International Association for the Study of Lung Cancer) of squamous and non-squamous histology, with progression on first line anti-PD1 immunotherapy.
  • Oligo-metastatic stage IV patients who received concurrent chemotherapy with thoracic radiation, followed by durvalumab consolidation and had progression of disease.
  • Locally advanced un-resectable NSCLC patients who received concurrent chemotherapy with thoracic radiation, followed by durvalumab consolidation and had progression of disease.
  • Males or females at least 18 years of age.
  • ECOG (Eastern Cooperative Oncology Group) performance status of 0 or 1.
  • Measureable disease by CT or MRI per RECIST 1.1 criteria.
Show all 20Show fewer
  • Life expectancy of at least 3 months.
  • Resolution of all clinically significant toxic effects of prior anticancer therapy to Grade ≤1 by the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), Version 4.0.
  • The participant must have adequate organ function, defined as:
  • Total bilirubin less than or equal to the upper limit of normal value (ULN), aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN, or ≤5 x ULN if the transferase elevation was due to liver metastases.
  • Serum creatinine ≤1.5 x ULN or calculated creatinine clearance ≥50 mL/min (per the Cockcroft-Gault formula or equivalent and/or 24-hour urine collection [Cockcroft-Gault glomerular filtration rate = (140-age) * (Wt in kg) * (0.85 if female) / (72 * Cr) where "Cr" is serum creatinine]).
  • Absolute neutrophil count (ANC) ≥1.5 x 103/μL (≥1.5 x 109/L), hemoglobin ≥10.0 g/dL (≥ 6.2 mmol/L), and platelets ≥100 x 103/μL (≥100 x 109/L).
  • International Normalized Ratio (INR) less than or equal to 1.5, or prothrombin time and partial thromboplastin time less than or equal to 1.5 x ULN.
  • The participant does not have 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 resulting from cirrhosis and requiring ongoing treatment with diuretics and/or paracentesis.
  • Urinary protein is ≤1+ on dipstick or routine urinalysis (UA). If urine dipstick or routine analysis indicated proteinuria ≥2+, then a 24-hour urine must be collected and must demonstrate <1000 mg of protein in 24 hours to allow participation in the study.
  • Female subjects must have a negative urine or serum pregnancy test at screening (within 72 hours of first dose of study medication) if of childbearing potential or be of non-child bearing potential.
  • If of childbearing potential, female subjects must be willing to use two adequate barrier methods throughout the study, starting with the screening visit through 180 days after last dose of chemotherapeutic agents.
  • Note: Abstinence is acceptable if this is the established and preferred contraception.
  • Male subjects with a female partner(s) of child-bearing potential must agree to use two adequate barrier methods throughout the trial starting with the screening visit through 180 days after the last dose of chemotherapy. Males with pregnant partners must agree to use a condom; no additional method of contraception is required for the pregnant partner.
  • The participant has voluntarily agreed to participate by giving written informed consent for the trial.

Who cannot join

  • Participant has received prior cytotoxic therapy or targeted oral agents for the treatment of their stage IV NSCLC. Participants with oligo-metastatic stage IV disease who received concurrent chemotherapy with thoracic radiation, followed by durvalumab consolidation with disease progression were eligible.
  • Participant has an EGFR (epidermal growth factor receptor) sensitizing mutation, ALK translocation and/or an ROS-1 gene rearrangement.
  • Participant has undergone major surgery within 28 days prior to screening, or subcutaneous venous access device placement within 7 days prior to screening. Furthermore, any partcipant with postoperative bleeding complications or wound complications from a surgical procedure performed in the last 2 months will be excluded.
  • Participant has untreated CNS (central nervous system) metastases. Participants with treated brain metastases were eligible if they were clinically stable with regard to neurologic function, off steroids after cranial irradiation (whole brain radiation therapy, focal radiation therapy, and stereotactic radiosurgery) ending at least 2 weeks prior to screening, or after surgical resection performed at least 28 days prior to screening. No evidence of Grade ≥1 CNS hemorrhage based on pretreatment MRI or IV contrast CT scan (performed within 21 days before screening).
  • There is radiologically documented evidence of major blood vessel invasion or encasement by cancer.
  • There is radiographic evidence of intra-tumor cavitation, regardless of tumor histology.
Show all 25Show fewer
  • Participant has a history of uncontrolled hereditary or acquired thrombotic disorder.
  • Participant has a history of gross hemoptysis (defined as bright red blood or ≥1/2 teaspoon) within 2months prior to screening.
  • Participant has clinically relevant congestive heart failure (CHF; NYHA II-IV) or symptomatic or poorly controlled cardiac arrhythmia.
  • Participant has experienced any arterial thrombotic event, including myocardial infarction, unstable angina, cerebrovascular accident, or transient ischemic attack, within 6 months prior to screening.
  • Participant has uncontrolled arterial hypertension ≥150 / ≥90 mm Hg despite standard medical management.
  • Participant has a serious or non-healing wound, ulcer, or bone fracture within 28 days prior to screening.
  • Participant has significant bleeding disorders, vasculitis, or experienced Grade 3-4 gastrointestinal (GI) bleeding within 3 months prior to screening.
  • History of GI perforation and/or fistulae within 6 months prior to screening.
  • Participant has bowel obstruction,history or presence of inflammatory enteropathy or extensive intestinal resection (hemicolectomy or extensive small intestine resection with chronic diarrhea), Crohn's disease, ulcerative colitis, or chronic diarrhea.
  • Participant has peripheral neuropathy ≥Grade 2 (NCI-CTCAE v 4.0).
  • Participant has a serious illness or medical condition(s) including, but not limited to, the following:
  • Known human immunodeficiency virus (HIV) infection or acquired immunodeficiency syndrome (AIDS)-related illness.
  • Active or uncontrolled clinically serious infection.
  • Previous or concurrent malignancy except for basal or squamous cell skin cancer and/or in situ carcinoma of the cervix, or other solid tumours treated curatively and without evidence of recurrence for at least 3 years prior to screening.
  • Uncontrolled metabolic disorders or other nonmalignant organ or systemic diseases or secondary effects of cancer that induced a high medical risk and/or made assessment of survival uncertain.
  • Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that might increase the risk associated with study participation or study drug administration, or might interfere with the interpretation of study results, and in the judgment of the investigator made the patient ineligible for entry into this study.
  • Participant has significant third-space fluid retention (for example, ascites or pleural effusion), and is not amenable for required repeated drainage.
  • Known allergy or hypersensitivity reaction to any of the treatment components.
  • Participant has a known history of active drug abuse.

Trial locations and contacts

1 site in 1 country.

United States1 site

  • Stony Brook University

    Stony Brook, New York, 11794

Other trials in United States

About this study

Official title: Phase-II Trial of Platinum-Based Chemotherapy Plus Ramucirumab in Patients With Advanced NSCLC Who Have Progressed on First Line Anti-PD-1 Immunotherapy

This is a non-randomized, phase-II study of platinum doublet chemotherapy plus ramucirumab in patients with advanced NSCLC who have progressed on first line anti-PD-1 Immunotherapy. Up to 25 evaluable participants will be enrolled over a period of 2 years. Seven patients will be recruited at the first stage .Eligible patients would include those treated with a PD-1 inhibitor as primary therapy and exhibit evidence of disease progression, but maintain a good performance status.

The investigators hypothesize that immune therapy acts as chemo-sensitizer and patients treated with standard platinum-based combination chemotherapy with the addition of the anti-angiogenic agent Ramucirumab, after immunotherapy will have higher response rates

Read the detailed description

OBJECTIVES:

Primary Objective

  1. To assess the objective response rate to a three-drug regimen (a platinum doublet plus an anti-angiogenic agent) in patients with non-small cell lung cancer who fail to respond, or progress after an initial response, to primary therapy with an immune checkpoint inhibitor.
  2. To assess the toxicity profile of the three-drug regimen in this population compared to historical treatment-naïve population (as published in literature)

Exploratory Objective

  1. To investigate the role of peripheral blood CD 8+ T cells, absolute eosinophil count (AEC) and circulating tumor cells (CTC) as biomarkers of response to salvage chemotherapy after primary immunotherapy
  2. To investigate the role of plasma carbonic anhydrase IX level as predictive biomarker of response to ramucirumab.
Being tested
Ramucirumab
Keywords
NSCLC, Immunotherapy, Ramucirumab, anti-PD-1
Medical subject headings
Carcinoma, Non-Small-Cell Lung

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • RamucirumabDrug

    Also called cyramza, BLA 125477

    platinum doublets chemotherapy plus ramucirumab, intravenously(IV)

Study groups in NCT03904108
Study groupRoleWhat they receive
RamucirumabExperimentalRamucirumab 10 mg/kg IV day 1, every 3 weeks for 4 cycles
Receives: Drug: Ramucirumab

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Objective Response Per RECIST 1.1 as Assessed by Central Imaging

    Objective response (OR) is the occurrence of CR or PR as the best overall response. OR will be based on responses confirmed using the subsequent 6-weekly scan. OR is based on the Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR.

    Measured: ≥18 weeks, up to maximum of 12 months

  2. Number of Participants With Treatment Related Dose Delay or Treatment Discontinuation

    Adverse events will be recorded in relation to each cycle of treatment and graded according to CTCAE criteria. The toxicity co-primary outcome measure for the trial is defined as the occurrence of a treatment-related dose delay or treatment discontinuation due to toxicity

    Measured: Through study completion, up to a maximum of 12 months. Serious AEs: Up to 90 days after last dose of study treatment, Other AEs: Up to 30 days after last dose of study treatment

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted4 Apr 2019
  2. Study start27 Jun 2019
  3. Primary completion27 Jul 2020
  4. Study completion27 Jul 2020

Why it stopped: insufficient patient population to complete trial as planned

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
3 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03904108
Sponsor's protocol ID
IRB2019-00094
Status last verified
Apr 2022
First submitted
2 Apr 2019
Last updated
26 May 2022
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017 Jan;67(1):7-30. doi: 10.3322/caac.21387. Epub 2017 Jan 5.

    PubMed 28055103

  • Schiller JH, Harrington D, Belani CP, Langer C, Sandler A, Krook J, Zhu J, Johnson DH; Eastern Cooperative Oncology Group. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med. 2002 Jan 10;346(2):92-8. doi: 10.1056/NEJMoa011954.

    PubMed 11784875

  • Sandler A, Gray R, Perry MC, Brahmer J, Schiller JH, Dowlati A, Lilenbaum R, Johnson DH. Paclitaxel-carboplatin alone or with bevacizumab for non-small-cell lung cancer. N Engl J Med. 2006 Dec 14;355(24):2542-50. doi: 10.1056/NEJMoa061884.

    PubMed 17167137

  • Sandler AB, Schiller JH, Gray R, Dimery I, Brahmer J, Samant M, Wang LI, Johnson DH. Retrospective evaluation of the clinical and radiographic risk factors associated with severe pulmonary hemorrhage in first-line advanced, unresectable non-small-cell lung cancer treated with Carboplatin and Paclitaxel plus bevacizumab. J Clin Oncol. 2009 Mar 20;27(9):1405-12. doi: 10.1200/JCO.2008.16.2412. Epub 2009 Feb 17.

    PubMed 19224857

  • Ramalingam SS, Dahlberg SE, Langer CJ, Gray R, Belani CP, Brahmer JR, Sandler AB, Schiller JH, Johnson DH; Eastern Cooperative Oncology Group. Outcomes for elderly, advanced-stage non small-cell lung cancer patients treated with bevacizumab in combination with carboplatin and paclitaxel: analysis of Eastern Cooperative Oncology Group Trial 4599. J Clin Oncol. 2008 Jan 1;26(1):60-5. doi: 10.1200/JCO.2007.13.1144.

    PubMed 18165641

  • Garon EB, Ciuleanu TE, Arrieta O, Prabhash K, Syrigos KN, Goksel T, Park K, Gorbunova V, Kowalyszyn RD, Pikiel J, Czyzewicz G, Orlov SV, Lewanski CR, Thomas M, Bidoli P, Dakhil S, Gans S, Kim JH, Grigorescu A, Karaseva N, Reck M, Cappuzzo F, Alexandris E, Sashegyi A, Yurasov S, Perol M. Ramucirumab plus docetaxel versus placebo plus docetaxel for second-line treatment of stage IV non-small-cell lung cancer after disease progression on platinum-based therapy (REVEL): a multicentre, double-blind, randomised phase 3 trial. Lancet. 2014 Aug 23;384(9944):665-73. doi: 10.1016/S0140-6736(14)60845-X. Epub 2014 Jun 2.

    PubMed 24933332

  • Camidge DR, Berge EM, Doebele RC, Ballas MS, Jahan T, Haigentz M Jr, Hoffman D, Spicer J, West H, Lee P, Yang L, Joshi A, Gao L, Yurasov S, Mita A. A phase II, open-label study of ramucirumab in combination with paclitaxel and carboplatin as first-line therapy in patients with stage IIIB/IV non-small-cell lung cancer. J Thorac Oncol. 2014 Oct;9(10):1532-9. doi: 10.1097/JTO.0000000000000273.

    PubMed 25170639

  • Doebele RC, Spigel D, Tehfe M, Thomas S, Reck M, Verma S, Eakle J, Bustin F, Goldschmidt J Jr, Cao D, Alexandris E, Yurasov S, Camidge DR, Bonomi P. Phase 2, randomized, open-label study of ramucirumab in combination with first-line pemetrexed and platinum chemotherapy in patients with nonsquamous, advanced/metastatic non-small cell lung cancer. Cancer. 2015 Mar 15;121(6):883-92. doi: 10.1002/cncr.29132. Epub 2014 Nov 6.

    PubMed 25377507

  • Brahmer J, Reckamp KL, Baas P, Crino L, Eberhardt WE, Poddubskaya E, Antonia S, Pluzanski A, Vokes EE, Holgado E, Waterhouse D, Ready N, Gainor J, Aren Frontera O, Havel L, Steins M, Garassino MC, Aerts JG, Domine M, Paz-Ares L, Reck M, Baudelet C, Harbison CT, Lestini B, Spigel DR. Nivolumab versus Docetaxel in Advanced Squamous-Cell Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Jul 9;373(2):123-35. doi: 10.1056/NEJMoa1504627. Epub 2015 May 31.

    PubMed 26028407

  • Borghaei H, Paz-Ares L, Horn L, Spigel DR, Steins M, Ready NE, Chow LQ, Vokes EE, Felip E, Holgado E, Barlesi F, Kohlhaufl M, Arrieta O, Burgio MA, Fayette J, Lena H, Poddubskaya E, Gerber DE, Gettinger SN, Rudin CM, Rizvi N, Crino L, Blumenschein GR Jr, Antonia SJ, Dorange C, Harbison CT, Graf Finckenstein F, Brahmer JR. Nivolumab versus Docetaxel in Advanced Nonsquamous Non-Small-Cell Lung Cancer. N Engl J Med. 2015 Oct 22;373(17):1627-39. doi: 10.1056/NEJMoa1507643. Epub 2015 Sep 27.

    PubMed 26412456

  • Herbst RS, Baas P, Kim DW, Felip E, Perez-Gracia JL, Han JY, Molina J, Kim JH, Arvis CD, Ahn MJ, Majem M, Fidler MJ, de Castro G Jr, Garrido M, Lubiniecki GM, Shentu Y, Im E, Dolled-Filhart M, Garon EB. Pembrolizumab versus docetaxel for previously treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised controlled trial. Lancet. 2016 Apr 9;387(10027):1540-1550. doi: 10.1016/S0140-6736(15)01281-7. Epub 2015 Dec 19.

    PubMed 26712084

  • Rittmeyer A, Barlesi F, Waterkamp D, Park K, Ciardiello F, von Pawel J, Gadgeel SM, Hida T, Kowalski DM, Dols MC, Cortinovis DL, Leach J, Polikoff J, Barrios C, Kabbinavar F, Frontera OA, De Marinis F, Turna H, Lee JS, Ballinger M, Kowanetz M, He P, Chen DS, Sandler A, Gandara DR; OAK Study Group. Atezolizumab versus docetaxel in patients with previously treated non-small-cell lung cancer (OAK): a phase 3, open-label, multicentre randomised controlled trial. Lancet. 2017 Jan 21;389(10066):255-265. doi: 10.1016/S0140-6736(16)32517-X. Epub 2016 Dec 13.

    PubMed 27979383

  • Reck M, Rodriguez-Abreu D, Robinson AG, Hui R, Csoszi T, Fulop A, Gottfried M, Peled N, Tafreshi A, Cuffe S, O'Brien M, Rao S, Hotta K, Leiby MA, Lubiniecki GM, Shentu Y, Rangwala R, Brahmer JR; KEYNOTE-024 Investigators. Pembrolizumab versus Chemotherapy for PD-L1-Positive Non-Small-Cell Lung Cancer. N Engl J Med. 2016 Nov 10;375(19):1823-1833. doi: 10.1056/NEJMoa1606774. Epub 2016 Oct 8.

    PubMed 27718847

  • Langer CJ, Gadgeel SM, Borghaei H, Papadimitrakopoulou VA, Patnaik A, Powell SF, Gentzler RD, Martins RG, Stevenson JP, Jalal SI, Panwalkar A, Yang JC, Gubens M, Sequist LV, Awad MM, Fiore J, Ge Y, Raftopoulos H, Gandhi L; KEYNOTE-021 investigators. Carboplatin and pemetrexed with or without pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. 2016 Nov;17(11):1497-1508. doi: 10.1016/S1470-2045(16)30498-3. Epub 2016 Oct 10.

    PubMed 27745820

  • Antonia SJ, Villegas A, Daniel D, Vicente D, Murakami S, Hui R, Yokoi T, Chiappori A, Lee KH, de Wit M, Cho BC, Bourhaba M, Quantin X, Tokito T, Mekhail T, Planchard D, Kim YC, Karapetis CS, Hiret S, Ostoros G, Kubota K, Gray JE, Paz-Ares L, de Castro Carpeno J, Wadsworth C, Melillo G, Jiang H, Huang Y, Dennis PA, Ozguroglu M; PACIFIC Investigators. Durvalumab after Chemoradiotherapy in Stage III Non-Small-Cell Lung Cancer. N Engl J Med. 2017 Nov 16;377(20):1919-1929. doi: 10.1056/NEJMoa1709937. Epub 2017 Sep 8.

    PubMed 28885881

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Ramucirumab in people with Carcinoma, Non-Small-Cell Lung, run by ROGER S KERESZTES MD at 1 site in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 25 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: stopped early, as of the sponsor's last update on 26 May 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 26 May 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Number of Participants With Objective Response Per RECIST 1.1 as Assessed by Central Imaging (time frame: ≥18 weeks, up to maximum of 12 months). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT03904108, which also lists 24 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 26 May 2022.

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