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

• ClinicalTrials.gov Identifier: NCT04300244
• Recruitment Status: Active, not recruiting
• First Posted: March 9, 2020
• Last Update Posted: February 29, 2024
• Sponsor: Åslaug Helland
• Collaborators: Oslo University Hospital; Ultimovacs ASA; Bristol-Myers Squibb
• Information provided by (Responsible Party): Åslaug Helland, Ullevaal University Hospital

Study Description

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.

Condition or disease	Intervention/treatment	Phase
Cancer; Cancer, Lung; Cancer of Lung; Mesothelioma; Mesothelioma; Lung; Mesothelioma; Pleura; Mesotheliomas Pleural	Biological: UV1 vaccine + leukine; Biological: ipilimumab; Biological: nivolumab	Phase 2

Detailed Description:

Several studies have investigated the use of checkpoint inhibition in Malign Pleural Mesothelioma (MPM). Most of them are small studies investigating the efficacy of single-agent immunotherapy in few patients. Given that the combination of anti-PD-1 or anti-PD-L1 therapy with CTLA-4 has been shown in other cancers to enhance treatment effect, combined checkpoint inhibitor treatment has also been investigated in patients with MPM. Although these results are encouraging, the response rates seen are moderate compared to what has been documented for the combination of checkpoint inhibitors in other cancer indications. An approach to further enhance the PFS and response rate in MPM may be to use a vaccine aiming to activate an immune response directed against tumor-related antigens, and to combine the vaccine with checkpoint inhibitors. The proposed study will evaluate the use of the therapeutic cancer vaccine UV1 in combination with nivolumab and ipilimumab after progression on standard first-line chemotherapy in patients with malignant pleural mesothelioma.

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

The primary end-point (PFS) is expected to be analyzed in 2023.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 118 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 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.
• Masking: None (Open Label)
• Masking Description: Open label
• Primary Purpose: Treatment
• Official Title: Nivolumab and Ipilimumab +/- UV1 Vaccination as Second Line Treatment in Patients With Malignant Mesothelioma (the NIPU-study)
• Actual Study Start Date: May 4, 2020
• Estimated Primary Completion Date: March 15, 2025
• Estimated Study Completion Date: March 15, 2027

Arms and Interventions

Arm	Intervention/treatment
Experimental: Arm A; Ipilimumab and nivolumab + UV1	Biological: UV1 vaccine + leukine; 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.; Biological: ipilimumab; The responses to ipilimumab and nivolumab combination therapy seen in MPM is encouraging.; Other Name: Yervoy; Biological: nivolumab; The responses to ipilimumab and nivolumab combination therapy seen in MPM is encouraging.; Other Name: Opdivo
Active Comparator: Arm B; Ipilimumab and nivolumab	Biological: ipilimumab; The responses to ipilimumab and nivolumab combination therapy seen in MPM is encouraging.; Other Name: Yervoy; Biological: nivolumab; The responses to ipilimumab and nivolumab combination therapy seen in MPM is encouraging.; Other Name: Opdivo

Outcome Measures

Primary Outcome Measures :

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

Secondary Outcome Measures :

1. Response evaluation [ Time Frame: Throughout the trial. Radiological assessments every 6th week during the first year, every 12th week for the next 5 years. ]
   Comparison of response rate according to Response Evaluation Criteria in Solid Tumors, version 1.1 (Modified RECIST), in patients who receive nivolumab and ipilimumab with patients who receive nivolumab and ipilimumab in combination with UV1.
2. Evaluation of patient reported outcomes (PRO) [ Time Frame: every other week for the first 12 weeks, every 6th week thereafter ]
   To evaluate changes from baseline in patient-reported outcomes (PROs) in patients who receive nivolumab and ipilimumab compared to patients who receive nivolumab and ipilimumab in combination with UV1.
3. Evaluation of Adverse Events and discontinuation rate of patients [ Time Frame: Continuously, and until 90 days after discontinuation of study treatment. ]

   To determine the safety and tolerability of patients receiving ipilimumab and nivolumab With or without UV1 vaccination by monitoring AEs and study drug discontinuation due to AEs.

   tolerability in patients who receive nivolumab and ipilimumab compared to patients who receive nivolumab and ipilimumab in combination with UV1, measured by adverse events (AE) and study drug discontinuations due to AEs.

Other Outcome Measures:

1. Assessment of repertoire of TCR specificities induced by UV1 vaccination [ Time Frame: blood samples collected at screening, week 6, week 12 and week 18/19. ]
   Generating TCR repertoire data and comparing differences pre- and post treatment between the two treatment arms
2. Investigate whether there is a correlation between baseline tumor mutational burden (TMB) and response to therapy [ Time Frame: In tissue collected at screening, week 5/6, and study completion, at most 2 years. ]
   Characterization of TMB pre- and post-treatment by DNA analyses of tumor and normal tissue to identify tumor-specific somatic mutations, and comparing results to clinical outcome data.
3. investigate whether there is a difference in the immune cell infiltrate in the tumor pre- and post treatment With UV1 and check point inhibition. [ Time Frame: In tissue collected at screening, week 5/6, and study completion, at most 2 years. ]
   By characterizing qualitative and quantitative differences in markers of immune activation within tumor samples pre and post therapy by immunohistochemistry.
4. Investigate whether UV1 vaccination induces hTERT-specific T cells in the blood of patients treated. [ Time Frame: blood samples collected at pre-defined evaluation points throughout study completion, at most 2 years. ]
   By detection of vaccine-specific T cells in PBMC harvested from patients by T cell proliferation assays
5. Investigate whether DTH response correlates With detection of a vaccine-specific T cell response in blood [ Time Frame: blood samples collected atat pre-defined evaluation points throughout study completion, at most 2 years. ]
   The trial will compare DTH measurements With vaccine-specific T-cell response in blood.
6. Investigate whether there is a correlation between the microenvironment in feces and treatment response. [ Time Frame: blood samples collected at at pre-defined evaluation points throughout study completion, at most 2 years. ]
   Stool samples will be collected and data on microbial gut composition for each patient will be correlated With treatment outcome.

Eligibility Criteria

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

Criteria

Inclusion Criteria:

• 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

  1. Haemoglobin ≥ 9.0 g/dL
  2. Absolute neutrophil count (ANC) 1.5 (or 1.0) x (> 1500 per mm3)
  3. Platelet count ≥100 (or 75) x 109/L (>75,000 per mm3)
  4. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN).
  5. 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

  6. Measured creatinine clearance (CL)

     1. >40 mL/min
     2. Calculated creatinine CL>40 mL/min (Cockcroft-Gault formula)
     3. 24-hour urinecollection for determination of CL
• Males: Creatinine CL (mL/min) =Weight (kg) x (140 - Age) 72 x serum creatinine (mg/dL)
• Females:Creatinine CL (mL/min)=Weight (kg) x (140 - Age)x0.85 72 x serum creatinine (mg/dL)
• Previously treated with at least one line of platinum -pemetrexed

Exclusion Criteria:

• 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.
• Any condition that, in the opinion of the investigator, would interfere with the evaluation of study treatment or interpretation of patient safety or study results.
• History of allergy or hypersensitivity to any of the active substances or excipients in the study drug.

Contacts and Locations

Locations

Australia

University of Western Australia

Perth, Australia

Denmark

Aalborg University Hospital

Aalborg, Denmark

Copenhagen University Hospital

Copenhagen, Denmark

Norway

Oslo University Hospital

Oslo, Norway

Spain

Vall d'Hebron institute of oncology

Barcelona, Spain

Sweden

University Hospital of Skåne

Lund, Sweden

Karolinska

Stockholm, Sweden

Sponsors and Collaborators

Åslaug Helland

Oslo University Hospital

Ultimovacs ASA

Bristol-Myers Squibb

Investigators

• Principal Investigator: Åslaug Helland, Prof, MD; Oslo University Hospital

More Information

Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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.

• Responsible Party: Åslaug Helland, MD, Prof, PhD, Ullevaal University Hospital
• ClinicalTrials.gov Identifier: NCT04300244
• Other Study ID Numbers: CA209-7H4 NIPU
• First Posted: March 9, 2020
• Last Update Posted: February 29, 2024
• Last Verified: February 2024

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Mesothelioma; Mesothelioma, Malignant; Lung Neoplasms; Adenoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Mesothelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Pleural Neoplasms; Lung Diseases; Respiratory Tract Diseases; Nivolumab; Ipilimumab; Sargramostim; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action; Immunologic Factors; Physiological Effects of Drugs