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Mesothelioma, MalignantPhase 2NCT03502746

Phase II Nivolumab and Ramucirumab for Patients With Previously-Treated Mesothelioma

A Phase 2 study testing Nivolumab and Ramucirumab in people with Mesothelioma, Malignant, run by Arkadiusz Z. Dudek, MD at 4 sites in United States.

Terminated

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

Official record
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Trial summary

This study will evaluate the combination of Nivolumab and Ramucirumab in patients with previously-treated mesothelioma. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Mesothelioma, Malignant
What is being tested?
Nivolumab and Ramucirumab
Type of treatment
Injection or infusion
Could I receive a placebo?
No, everyone receives an active treatment
How many people
34 participants
Where
4 sitesUnited States
Study dates
26 Jun 2018to 9 Nov 2023
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

  • Male or female ≥ 18 years of age at time of consent.
  • Histologically-confirmed malignant mesothelioma not amenable to curative surgery and who have received at least one pemetrexed-containing chemotherapy regimen.
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.
  • total bilirubin < 1.5 mg/dL (25.65 μmol/L) OR direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 mg/dL (except subject with Gilbert's Syndrome, who can have total bilirubin < 3.0 mg/dl)
  • aspartate aminotransferase (AST) ≤ 3 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases
  • alanine aminotransferase (ALT) ≤ 3 × ULN or ≤ 5 × ULN for subjects with known hepatic metastases
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  • hemoglobin ≥ 8 g/dL, subjects requiring transfusion will not be eligible to start study
  • absolute neutrophil count (ANC) ≥ 1.5 × 109/L
  • platelet count ≥ 100 × 109/L
  • serum creatinine ≤1.5 times the 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)
  • subject'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)
  • INR < 1.5, and a partial thromboplastin time (PTT) (PTT/aPTT) < 1.5 x ULN (unless receiving anticoagulant therapy)
  • Subjects on full-dose anticoagulation must be on a stable dose (minimum duration 14 days) of oral anticoagulant or low molecular weight heparin (LMWH). Patients receiving warfarin must be switched to low molecular weight heparin and have achieved stable coagulation profile prior to first dose of protocol therapy. For heparin and LMWH there should be no active bleeding (that is, no bleeding within 14 days prior to first dose of protocol therapy) or pathological condition present that carries a high risk of bleeding (for example, tumor involving major vessels or known varices).
  • Subjects must be willing to undergo a CT-guided biopsy (i.e., image-guided percutaneous lung biopsy) to obtain tumor tissue within 28 days before initiation of treatment and after 4 cycles (8 weeks) of treatment.
  • Women of childbearing potential (WOCP) must be willing to use birth control as outlined in the protocol.
  • Men who are not surgically or medically sterile must agree to use contraception as outlined in the protocol.
  • Measurable disease, defined as at least 1 tumor that fulfills the criteria for a target lesion according to modified RECIST 1.1 criteria, and obtained by imaging within 28 days prior to study registration.
  • Prior intracavity cytotoxic or sclerosing agents (including bleomycin) is acceptable.
  • Radiation therapy must be completed > 28 days before study registration, and the measurable disease must be outside of the radiation port.
  • Pemetrexed-containing chemotherapy must be completed > 28 days before study registration.
  • Must provide written informed consent and HIPAA authorization approved by an Institutional Review Board (IRB). NOTE: HIPAA authorization may be included in the informed consent or obtained separately.
  • All previous toxicity resolved to Grade 1 or less.

Who cannot join

  • Any Grade 3-4 GI bleeding within 3 months prior to study registration.
  • History of deep vein thrombosis, pulmonary embolism, or any other significant thromboembolism (venous port or catheter thrombosis or superficial venous thrombosis are not considered "significant") during the 3 months prior to study registration.
  • Any arterial thromboembolic events, including but not limited to myocardial infarction, transient ischemic attack, cerebrovascular accident, or unstable angina, within 6 months prior to study registration.
  • Cirrhosis at a level of Child-Pugh B (or worse), or cirrhosis (any degree) with 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.
  • Uncontrolled or poorly-controlled hypertension (>160 mmHg systolic or > 100 mmHg diastolic for >4 weeks) despite standard medical management.
  • Prior history of GI perforation/fistula (within 6 months of study registration) or risk factors for perforation.
Show all 32Show fewer
  • Serious or nonhealing wound, ulcer, or bone fracture within 28 days prior to study registration.
  • Active brain metastases or carcinomatous meningitis. Subjects with neurological symptoms must undergo a head CT scan or brain MRI to exclude brain metastasis. Subjects with previously treated brain metastases may participate provided they are stable (without evidence of progression by imaging for at least four weeks prior to the first dose of study drugs and any neurologic symptoms have returned to baseline), have no evidence of new or enlarging brain metastases, and are not using steroids for at least 14 days prior to study registration. This exception does not include carcinomatous meningitis, which is excluded regardless of clinical stability.
  • Major surgery within 28 days prior to study registration
  • Subcutaneous venous access device placement within 7 days prior to study registration.
  • Elective or planned major surgery to be performed during the course of the clinical trial.
  • 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.
  • Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS). NOTE: HIV testing is not required.
  • Known history of testing positive for hepatitis B virus surface antigen (HBV sAg) or hepatitis C virus ribonucleic acid (HCV antibody), indicating acute or chronic infection. NOTE: Hepatitis B and Hepatitis C testing is not required.
  • Condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
  • Active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Subjects are permitted to enroll if they have vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, psoriasis not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger.
  • o NOTE: Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment.
  • Received a live vaccine within 30 days prior to the first dose of trial treatment. Examples of live vaccines include, but are not limited to: measles, mumps, rubella, chicken pox, yellow fever, rabies, BCG, and typhoid (oral) vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g. Flu-Mist®) are live attenuated vaccines and are not allowed.
  • History of interstitial lung disease or active, non-infectious pneumonitis.
  • Female subject is pregnant or breast-feeding.
  • NOTE: Women of childbearing potential (WOCP) must have a negative pregnancy test (either serum β-HCG with a sensitivity of 50 mIU/ml or urine dipstick within 24 hours of study registration).
  • NOTE: Women are not considered to be of childbearing potential if they meet at least one of the following: 1) surgically sterilized, or 2) postmenopausal (a woman who is ≥45 years of age and has not had menses for greater than 1 year), or 3) not heterosexually active for the duration of the study. See section 5.6.2.
  • Major blood vessel invasion or significant intratumor cavitation.
  • If they experience hemoptysis (defined as bright red blood or ≥ ½ 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.
  • Any condition that, in the opinion of the investigator, might jeopardize the safety of the subject or interfere with protocol compliance.
  • Any mental or medical condition that prevents the subject from giving informed consent or participating in the trial.
  • Any pathological condition that carries a high risk of bleeding (for example, tumor involving major vessels or known varices.)
  • Known hypersensitivity to nivolumab or ramucirumab or any of their components.
  • Known history of active tuberculosis.
  • Received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-Cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody (including ipilimumab or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).
  • No prior malignancy is allowed except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, localized Gleason ≤ grade 7 prostate cancers. Subjects with other solid tumors treated curatively and without evidence of recurrence for at least 3 years prior to enrollment may be eligible for study after discussion with the sponsor-investigator
  • Treatment with any investigational agent within 28 days prior to study registration. The subject must have recovered from the acute toxic effects of the regimen.

Trial locations and contacts

4 sites in 1 country.

United States4 sites

  • University of Maryland

    Baltimore, Maryland, 21201

  • Karmanos Cancer Center (Wayne State University)

    Detroit, Michigan, 48201

  • HealthPartners Institute Regions Cancer Care Center

    Minneapolis, Minnesota, 55440

  • Moffitt Cancer Center

    Tampa, Florida, 33612

Other trials in United States

About this study

Official title: Phase II Study of Nivolumab and Ramucirumab for Patients With Previously-Treated Mesothelioma:Hoosier Cancer Research Network LUN15-299

This study will evaluate the combination of Nivolumab and Ramucirumab in patients with previously-treated mesothelioma.

Read the detailed description

The programmed death ligand 1 (PD-L1) [16] and VEGFR2 [34] are highly-expressed on mesothelioma cells, and are therefore attractive options for this cancer. We chose to study the combination of ramucirumab with nivolumab because of the potential efficacy of these two agents in mesothelioma and because of the potential synergistic activity between them [30]. As previously discussed, immunotherapies such as anti-PD-1 inhibitors must contend with a hostile, immunosuppressive tumor microenvironment due to angiogenesis that results in hypoxia. This hypoxia decreases the ability of antibodies to infiltrate the tumor. We hypothesize that the normalization of tumor vasculature (by reducing the area of the tumor that is hypoxic) with an anti-VEGF strategy (i.e., ramucirumab) used in synergy with a PD-1 inhibitor will facilitate the infiltration of T-lymphocytes into tumor parenchyma. We will conduct a phase II study based on this premise using nivolumab and ramucirumab as second-line therapy in patients with malignant mesothelioma who have failed standard doublet platinum and anti-folate therapy.

Being tested
Nivolumab, Ramucirumab
Medical subject headings
Mesothelioma, Malignant

What participants receive

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

  • NivolumabDrug

    Also called Opdivo

    Nivolumab 240mg, IV over 30 minutes.

  • RamucirumabDrug

    Also called Cyramza

    8mg/kg, IV over 60 minutes.

Study groups in NCT03502746
Study groupRoleWhat they receive
Nivolumab + RamucirumabExperimentalNivolumab 240mg IV + Ramucirumab 8mg/kg IV
Receives: Drug: Nivolumab; Drug: Ramucirumab

What is being measured

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

  1. Response Rate

    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) >= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. Response rate will be defined as the proportion of all subjects with confirmed PR or CR according to RECIST 1.1.

    Measured: Up to a maximum of 23 months

Secondary outcomes (3)

  1. Adverse Event Assessment

    The frequency and severity of all grade ≥ 2 treatment related adverse events are reported by CTCAE v4 term.

    Measured: AE had been recorded from time of consent until 100 days after discontinuation of study drug or until a new anti-cancer treatment starts, whichever occurs first; up to a maximum of 28 months.

  2. Progression-free Survival (PFS)

    Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST): Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progressive Disease (PD) >= 20% increase in tumor burden relative to nadir or the appearance of one or more new lesions; Stable Disease (SD), not meet criteria for CR/PR/PD. PFS is defined as time from treatment start until disease progression met by RECIST 1.1 or death from any cause.

    Measured: Time of treatment start until the criteria for disease progression or death, up to a maximum of 23 months.

  3. Overall Survival

    Overall survival (OS) is defined as time of treatment start until death or date of last contact.

    Measured: Time of treatment start until death or date of last contact, up to a maximum of 32 months.

Timeline

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

  1. First posted19 Apr 2018
  2. Study start26 Jun 2018
  3. Primary completion11 May 2022
  4. Study completion9 Nov 2023

Why it stopped: IRB Study Closure

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
34 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT03502746
Sponsor's protocol ID
HCRN-LUN15-299
Status last verified
Apr 2024
First submitted
11 Apr 2018
Last updated
14 May 2024
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No
Individual data sharing
No

Publications

  • Dudek AZ, Xi MX, Scilla KA, Mamdani H, Creelan BC, Saltos A, Tanvetyanon T, Chiappori A. Phase 2 Trial of Nivolumab and Ramucirumab for Relapsed Mesothelioma: HCRN-LUN15-299. JTO Clin Res Rep. 2023 Oct 12;4(12):100584. doi: 10.1016/j.jtocrr.2023.100584. eCollection 2023 Dec.

    PubMed 38046376

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Nivolumab and Ramucirumab in people with Mesothelioma, Malignant, run by Arkadiusz Z. Dudek, MD at 4 sites 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 22 inclusion and 32 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 14 May 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites 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 Oct 2023). 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?

Response Rate (time frame: Up to a maximum of 23 months). 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 NCT03502746, which also lists 1 linked publication.

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 14 May 2024.

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