Nivolumab and Ipilimumab +/- UV1 Vaccination as Second Line Treatment in Patients With Malignant Mesothelioma

NCT04300244 | Active Not Recruiting Phase 2 DMC

• 1 other identifier: CA209-7H4 NIPU
• Study Type: interventional
• Target: 118
• Locations: 5 countries
• Sites: 7

Brief Summary

The objective of the study is to induce a meaningful progression-free survival benefit in patients with Malign Pleural Mesothelioma (MPM) after progression on first line standard platinum doublet chemotherapy, by treating with nivolumab and ipilimumab with or without UV1 vaccine.

Conditions

Cancer; Cancer, Lung; Cancer of Lung; Mesothelioma; Mesothelioma; Lung; Mesothelioma; Pleura; Mesotheliomas Pleural

Outcome Measures

Primary Outcomes (1)

• Evaluation of efficacy of ipilimumab and nivolumab With or without UV1 vaccine in patients With inoperable malignant pleural mesothelioma progressing after first-line platinum-based chemotherapy.

  Progression-free survival (PFS) per Modified Response Evaluation Criteria in Solid Tumors (RECIST) as determined by blinded independent central review (BICR) assessed by radiologic assessments

  Monitoring for change in imaging evalated tumor lesions indicating progression throughout the trial until 5 years of follow-up has past.

Secondary Outcomes (3)

• Response evaluation

  Throughout the trial. Radiological assessments every 6th week during the first year, every 12th week for the next 5 years.

• Evaluation of patient reported outcomes (PRO)

  every other week for the first 12 weeks, every 6th week thereafter

• Evaluation of Adverse Events and discontinuation rate of patients

  Continuously, and until 90 days after discontinuation of study treatment.

Other Outcomes (6)

• Assessment of repertoire of TCR specificities induced by UV1 vaccination

  blood samples collected at screening, week 6, week 12 and week 18/19.

• Investigate whether there is a correlation between baseline tumor mutational burden (TMB) and response to therapy

  In tissue collected at screening, week 5/6, and study completion, at most 2 years.

• investigate whether there is a difference in the immune cell infiltrate in the tumor pre- and post treatment With UV1 and check point inhibition.

  In tissue collected at screening, week 5/6, and study completion, at most 2 years.

Study Arms (2)

Arm A

EXPERIMENTAL

Ipilimumab and nivolumab + UV1

Biological: UV1 vaccine + leukine; Biological: ipilimumab; Biological: nivolumab

Arm B

ACTIVE COMPARATOR

Ipilimumab and nivolumab

Biological: ipilimumab; Biological: nivolumab

Interventions

UV1 vaccine + leukine BIOLOGICAL

The mode of action of UV1 is to activate the immune system to induce T cells directed against telomerase (hTERT). UV1 vaccination amplifies the pool of hTERT specific tumor-reactive T cells from the naive repertoire and has the potential to increase the breadth and diversity of the tumor-reactive T cell response (epitope spreading). Vaccination with UV1 can thus provide the basis for increased efficacy of checkpoint inhibition therapy, by augmenting the pool of tumor specific T cells in patients with limited or insufficient numbers of T cell clones spontaneously primed by tumor antigens. Reciprocally, the efficacy of UV1 vaccination may be enhanced in combination with checkpoint inhibitors, since the clonal expansion and effector activity of UV1 induced T cells will otherwise be restricted by intrinsic immune regulatory and tumor induced suppressor mechanisms.

Arm A

ipilimumab BIOLOGICAL

The responses to ipilimumab and nivolumab combination therapy seen in MPM is encouraging.

Also known as: Yervoy

Arm A; Arm B

nivolumab BIOLOGICAL

The responses to ipilimumab and nivolumab combination therapy seen in MPM is encouraging.

Also known as: Opdivo

Arm A; Arm B

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically and/or cytologically confirmed malignant pleural mesothelioma.
• Unresectable disease
• Measurable disease, defined as at least 1 lesion (measurable) that can be accurately assessed at baseline by computed tomography (CT) or magnetic resonance imaging (MRI) and is suitable for repeated assessment (modified RECIST).
• Available unstained archived tumor tissue sample in sufficient quantity to allow for analyses. At least fifteen unstained slides or a tumor block (preferred). NOTE: A fine needle aspiration sample is not sufficient to make the patient eligible for enrollment. Given the complexity of mesothelioma pathological diagnosis , it is expected that they will have a core needle biopsy or surgical tumor biopsy as part of their initial diagnostic work up.
• Age ≥ 18 years.
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 - 1.
• Willing to provide archived tumor tissue and blood samples for research.
• Adequate organ function as defined below
• Haemoglobin ≥ 9.0 g/dL
• Absolute neutrophil count (ANC) 1.5 (or 1.0) x (\> 1500 per mm3)
• Platelet count ≥100 (or 75) x 109/L (\>75,000 per mm3)
• Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
• AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver metastases are present, in which case it must be ≤5x ULN
• Measured creatinine clearance (CL)
• \>40 mL/min

You may not qualify if:

• Disease suitable for curative surgery
• Previous treatment with a PD-1 or PD-L1 inhibitor, including nivolumab or any other agent targeting immune checkpoints.
• Non-pleural mesothelioma e.g. mesothelioma arising in peritoneum, tunica vaginalis or any serosal surface other than the pleura.
• Active second malignancy other than non-melanoma skin cancer or cervical carcinoma in situ.
• Symptomatic or uncontrolled brain metastases requiring concurrent treatment, inclusive of but not limited to surgery, radiation and/or corticosteroids (prednisone \>10 mg or equivalent). Surgery, radiation and/or corticosteroids (any dose \>10 mg prednisone equivalent) must have been completed ≥ 2 weeks prior to registration.
• Uncontrolled seizures.
• Current or prior use of immunosuppressive medication within 28 days before the first dose of nivolumab, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Standard steroid premedication given prior to chemotherapy or as prophylaxis for imaging contrast allergy should not be counted for this criterion.
• Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease; Wegner syndrome) within the past 2 years. Subjects with vitiligo, alopecia, Grave's disease, or psoriasis not requiring systemic treatment (within the past 3 years) are not excluded.
• History of primary immunodeficiency.
• History of allogeneic organ transplant.
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, active bleeding diatheses including any subject known to have psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent.
• Active infection including tuberculosis (clinical evaluation including: physical examination findings, radiographic findings, positive PPD test, etc.), hepatitis B (known positive HBV surface antigen \[HBsAg\] result), hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies as defined by a positive ELISA test). Patients with a past or resolved HBV infection (defined as the presence of hepatitis B core antibody \[anti-HBc\] and absence of HBsAg) are eligible. Patients positive for hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative for HCV RNA. HIV testing is not required in the absence of clinical suspicion.
• Known history of leptomeningeal carcinomatosis.
• Pregnant or lactating women
• Live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving nivolumab.

Sponsors & Collaborators

• Åslaug Helland: lead
• Oslo University Hospital: collaborator
• Ultimovacs ASA: collaborator
• Bristol-Myers Squibb: collaborator

Study Sites (7)

University of Western Australia

Perth, Australia

Location

Aalborg University Hospital

Aalborg, Denmark

Location

Copenhagen University Hospital

Copenhagen, Denmark

Location

Oslo University Hospital

Oslo, Norway

Location

Vall d'Hebron institute of oncology

Barcelona, Spain

Location

University Hospital of Skåne

Lund, Sweden

Location

Karolinska

Stockholm, Sweden

Location

Related Publications (2)

• Thunold S, Hernes E, Farooqi S, Ojlert AK, Francis RJ, Nowak AK, Szejniuk WM, Nielsen SS, Cedres S, Perdigo MS, Sorensen JB, Meltzer C, Mikalsen LTG, Helland A, Malinen E, Haakensen VD. Outcome prediction based on [18F]FDG PET/CT in patients with pleural mesothelioma treated with ipilimumab and nivolumab +/- UV1 telomerase vaccine. Eur J Nucl Med Mol Imaging. 2025 Jan;52(2):693-707. doi: 10.1007/s00259-024-06853-0. Epub 2024 Aug 12.

  PMID: 39133306 DERIVED

• Haakensen VD, Nowak AK, Ellingsen EB, Farooqi SJ, Bjaanaes MM, Horndalsveen H, Mcculloch T, Grundberg O, Cedres SM, Helland A. NIPU: a randomised, open-label, phase II study evaluating nivolumab and ipilimumab combined with UV1 vaccination as second line treatment in patients with malignant mesothelioma. J Transl Med. 2021 May 31;19(1):232. doi: 10.1186/s12967-021-02905-3.

  PMID: 34059094 DERIVED

MeSH Terms

Conditions

Neoplasms; Lung Neoplasms; Mesothelioma; Mesothelioma, Malignant

Interventions

UV1 vaccine; sargramostim; Ipilimumab; Nivolumab

Condition Hierarchy (Ancestors)

Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Lung Diseases; Respiratory Tract Diseases; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Mesothelial; Pleural Neoplasms

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Åslaug Helland, Prof, MD

  Oslo University Hospital

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Open label
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD, Prof, PhD

Model Details: randomized, multi-center, open-label, proof of concept study comparing the efficacy and safety of nivolumab and ipilimumab with or without UV1 in patients with inoperable malignant pleural mesothelioma after first-line platinum-based chemotherapy.

Study Record Dates

• First Submitted: February 19, 2020
• First Posted: March 9, 2020
• Study Start: May 4, 2020
• Primary Completion: March 15, 2025
• Study Completion (Estimated): March 15, 2027
• Last Updated: February 29, 2024

Record last verified: 2024-02

Locations

ES (1); NO (1); DK (2); SE (2); AU (1)