Clinical trial NCT04300244: Nivolumab and Ipilimumab +/- UV1 Vaccination as Second Line Treatment in Patients With Malignant Mesothelioma
Official title: Nivolumab and Ipilimumab +/- UV1 Vaccination as Second Line Treatment in Patients With Malignant Mesothelioma (the NIPU-study)
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE2
Conditions: Cancer
Cancer, Lung
Cancer of Lung
Mesothelioma
Mesothelioma; Lung
Mesothelioma; Pleura
Mesotheliomas Pleural
Lead sponsor: Oslo University Hospital
Sponsor class: OTHER
Collaborators: name: Oslo University Hospital
name: Ultimovacs ASA
name: Bristol-Myers Squibb
First posted: 2020-03-09
Enrollment: 118
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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.

Primary outcomes:
measure: 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.
timeFrame: Monitoring for change in imaging evalated tumor lesions indicating progression throughout the trial until 5 years of follow-up has past.
Secondary outcomes:
measure: Response evaluation
timeFrame: Throughout the trial. Radiological assessments every 6th week during the first year, every 12th week for the next 5 years.
measure: Evaluation of patient reported outcomes (PRO)
timeFrame: every other week for the first 12 weeks, every 6th week thereafter
measure: Evaluation of Adverse Events and discontinuation rate of patients
timeFrame: Continuously, and until 90 days after discontinuation of study treatment.
Other outcomes:
measure: Assessment of repertoire of TCR specificities induced by UV1 vaccination
timeFrame: blood samples collected at screening, week 6, week 12 and week 18/19.
measure: Investigate whether there is a correlation between baseline tumor mutational burden (TMB) and response to therapy
timeFrame: In tissue collected at screening, week 5/6, and study completion, at most 2 years.
measure: investigate whether there is a difference in the immune cell infiltrate in the tumor pre- and post treatment With UV1 and check point inhibition.
timeFrame: In tissue collected at screening, week 5/6, and study completion, at most 2 years.
measure: Investigate whether UV1 vaccination induces hTERT-specific T cells in the blood of patients treated.
timeFrame: blood samples collected at pre-defined evaluation points throughout study completion, at most 2 years.
measure: Investigate whether DTH response correlates With detection of a vaccine-specific T cell response in blood
timeFrame: blood samples collected atat pre-defined evaluation points throughout study completion, at most 2 years.
measure: Investigate whether there is a correlation between the microenvironment in feces and treatment response.
timeFrame: blood samples collected at at pre-defined evaluation points throughout study completion, at most 2 years.
Locations:
city: Perth
country: Australia
facility: University of Western Australia
city: Aalborg
country: Denmark
facility: Aalborg University Hospital
city: Copenhagen
country: Denmark
facility: Copenhagen University Hospital
city: Oslo
country: Norway
facility: Oslo University Hospital
city: Barcelona
country: Spain
facility: Vall d'Hebron institute of oncology
city: Lund
country: Sweden
facility: University Hospital of Skåne
city: Stockholm
country: Sweden
facility: Karolinska
Study officials:
affiliation: Oslo University Hospital
name: Åslaug Helland, Prof, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.