Clinical Trials /

Anetumab Ravtansine With Nivolumab, Ipilimumab and Gemcitabine Hydrochloride in Treating Patients With Mesothelin Positive Advanced Pancreatic Cancer

NCT03816358

Description:

This phase I trial studies the side effects and best dose of anetumab ravtansine when given together with nivolumab, ipilimumab and gemcitabine hydrochloride in treating patients with mesothelin positive pancreatic cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as anetumab ravtansine, nivolumab, and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Gemcitabine hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving anetumab ravtansine together with nivolumab, ipilimumab, and gemcitabine hydrochloride may work better in treating patients with pancreatic cancer.

Related Conditions:
  • Pancreatic Adenocarcinoma
Recruiting Status:

Suspended

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Anetumab Ravtansine With Nivolumab, Ipilimumab and Gemcitabine Hydrochloride in Treating Patients With Mesothelin Positive Advanced Pancreatic Cancer
  • Official Title: A Phase I Study of Anetumab Ravtansine in Combination With Either Anti-PD-1 Antibody, or Anti-CTLA4 and Anti-PD-1 Antibodies or Anti-PD-1 Antibody and Gemcitabine in Mesothelin-Positive Advanced Pancreatic Adenocarcinoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-00242
  • SECONDARY ID: NCI-2019-00242
  • SECONDARY ID: PJC-026
  • SECONDARY ID: 10208
  • SECONDARY ID: 10208
  • SECONDARY ID: UM1CA186644
  • NCT ID: NCT03816358

Conditions

  • Mesothelin Positive
  • Metastatic Pancreatic Adenocarcinoma
  • Recurrent Pancreatic Adenocarcinoma
  • Stage II Pancreatic Cancer AJCC v8
  • Stage IIA Pancreatic Cancer AJCC v8
  • Stage IIB Pancreatic Cancer AJCC v8
  • Stage III Pancreatic Cancer AJCC v8
  • Unresectable Pancreatic Carcinoma

Interventions

DrugSynonymsArms
Anetumab RavtansineBAY 94-9343Arm I (anetumab ravtansine, nivolumab)
Gemcitabine HydrochloridedFdCyd, Difluorodeoxycytidine Hydrochloride, Gemzar, LY-188011, LY188011Arm III (anetumab ravtansine, nivolumab, gemcitabine)
IpilimumabAnti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody, BMS-734016, MDX-010, MDX-CTLA4, YervoyArm II (anetumab ravtansine, nivolumab, ipilimumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm I (anetumab ravtansine, nivolumab)

Purpose

This phase I trial studies the side effects and best dose of anetumab ravtansine when given together with nivolumab, ipilimumab and gemcitabine hydrochloride in treating patients with mesothelin positive pancreatic cancer that has spread to other places in the body. Immunotherapy with monoclonal antibodies, such as anetumab ravtansine, nivolumab, and ipilimumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Gemcitabine hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving anetumab ravtansine together with nivolumab, ipilimumab, and gemcitabine hydrochloride may work better in treating patients with pancreatic cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To evaluate the safety and tolerability of anetumab ravtansine with the following
      combinations in patients with mesothelin positive pancreatic adenocarcinoma.

      SECONDARY OBJECTIVES:

      I. To assess the preliminary anti-tumor activity of anetumab ravtansine (anetumab) in
      combination with nivolumab, nivolumab and ipilimumab, nivolumab and gemcitabine hydrochloride
      (gemcitabine) as measured by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
      overall response rate (ORR).

      II. To characterize the pharmacokinetics (PK) profile of anetumab (apparent diffusion
      coefficient [ADC]), total antibody (ADC and cleaved free antibody), DM4 and DM4-Me (S-Methyl
      metabolite of DM4).

      III. To evaluate the tumor microenvironment and immune changes in tumor and peripheral blood
      over the course of treatment to identify predictors of response or resistance to treatment.

      IV. To measure the progressive disease (PD) effects of this combination including molecular
      and immune biomarkers in tumor biopsies and peripheral blood.

      EXPLORATORY OBJECTIVES:

      I. To characterize mesothelin, PD-L1, CD3, CD4, CD8 expressions at baseline and after
      treatment in mesothelin positive pancreatic cancer patients.

      II. To evaluate level of soluble mesothelin and megakaryocyte potentiation factor (MPF) over
      the course of treatment and to correlate these biomarkers with clinical outcome.

      III. To perform whole exome sequencing (WES) +/- ribonucleic acid sequencing (RNAseq) in the
      tumor biopsy specimens and correlation genomic (e.g. mutational burden) and transcriptomic
      biomarkers with clinical outcome.

      IV. To evaluate mononuclear phagocyte system (MPS) function, Fc-gamma receptors (FcgammaRs)
      and hormone and chemokine mediators as methods to evaluate factors affecting the PK and PD of
      these agents.

      V. To evaluate anti-drug antibody (ADA) titres changes pre and post treatment and correlate
      them with PK, toxicity and responses.

      OUTLINE: This is a dose-escalation study of anetumab ravtansine. Patients are assigned to 1
      of 3 arms.

      ARM I: Patients receive anetumab ravtansine intravenously (IV) over 1 hour and nivolumab IV
      over 30 minutes on day 1. Treatment repeats every 21 days for up to 17 cycles in the absence
      of disease progression or unacceptable toxicity.

      ARM II: Patients receive anetumab ravtansine IV over 1 hour and nivolumab IV over 30 minutes
      on day 1 and ipilimumab over 30 minutes IV on day 1 of courses 1-4. Treatment repeats every
      21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.

      ARM III: Patients receive anetumab ravtansine IV over 1 hour and nivolumab IV over 30 minutes
      on day 1 and gemcitabine hydrochloride over 30-40 minutes on days 1 and 8. Treatment repeats
      every 21 days in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at days 30-37 and then every 8
      weeks for up to 100 days.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (anetumab ravtansine, nivolumab)ExperimentalPatients receive anetumab ravtansine IV over 1 hour and nivolumab IV over 30 minutes on day 1. Treatment repeats every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.
  • Anetumab Ravtansine
  • Nivolumab
Arm II (anetumab ravtansine, nivolumab, ipilimumab)ExperimentalPatients receive anetumab ravtansine IV over 1 hour and nivolumab IV over 30 minutes on day 1 and ipilimumab over 30 minutes IV on day 1 of courses 1-4. Treatment repeats every 21 days for up to 17 cycles in the absence of disease progression or unacceptable toxicity.
  • Anetumab Ravtansine
  • Ipilimumab
  • Nivolumab
Arm III (anetumab ravtansine, nivolumab, gemcitabine)ExperimentalPatients receive anetumab ravtansine IV over 1 hour and nivolumab IV over 30 minutes on day 1 and gemcitabine hydrochloride over 30-40 minutes on days 1 and 8. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity.
  • Anetumab Ravtansine
  • Gemcitabine Hydrochloride
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically or cytologically confirmed pancreatic adenocarcinoma

          -  Only subjects with positive mesothelin expression (Ventana mesothelin [MSLN]-
             immunohistochemistry [IHC]; Negative=H-score =< 10) are eligible. This is to be
             performed centrally. For dose escalation cohorts, patients with mesothelin expression
             in >= 5% of tumor cells are eligible. For dose expansion, patients must have moderate
             or strong tumor mesothelin expression defined as mesothelin expression positive in >=
             30% of tumor cells on immunohistochemical staining

          -  Patients with un-resectable/recurrent/metastatic disease must have received and either
             progressed or been intolerant to at least 1 systemic therapy in the metastatic setting

          -  Life expectancy of at least 3 months

          -  Eastern Cooperative Oncology Group (ECOG) performance status score 0-1 (Karnofsky >=
             60%)

          -  Prior anti-cancer treatments are permitted (i.e. chemotherapy, including gemcitabine
             and nab-paclitaxel; radiotherapy; hormonal, or immunotherapy with the exception of
             anti-CTLA4, anti-PD1/PD-L1, and combination of anti-CTLA4 and anti-PD1/PD-L1)
             providing toxicity (except for alopecia) related to prior anti-cancer therapy and/or
             surgery have either resolved, improved to baseline or G1 or been deemed irreversible

          -  At least one (1) measurable lesion at baseline by computed tomography (CT) or magnetic
             resonance imaging (MRI) as per RECIST version (v)1.1; measurable disease is a
             requirement in both dose escalation phase and dose expansion phase

               -  Note: Measurable lesions may be in an irradiated field as long as there is
                  documented progression and the lesion(s) can be reproducibly measured

          -  At least one lesion safely accessible for biopsy unless medically contraindicated;
             biopsies are mandatory both in dose escalation and in dose expansion; in dose
             escalation and in expansion the following biopsies are optional: at baseline and at
             progression; biopsy could be: core needle or excisional or punch biopsy. Irradiated
             lesions can be biopsied if tumor growth is confirmed

          -  Patients must have archival tumor tissue for mesothelin expression and correlative
             biomarker studies; subjects must consent to provide tumor blocks or slides and the
             availability of the tissue must be confirmed prior to subjects receiving study
             medication; if an archived tumor specimen is unavailable or unsuitable for correlative
             biomarker studies, a pre-treatment fresh tumor biopsy is required

          -  Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy
             test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours of study
             enrollment or randomization; WOCBP must agree to appropriate methods of contraception
             for the duration of treatment and for 6 months after completion of treatment; Males
             who are sexually active with a partner of childbearing potential must agree to
             appropriate methods of contraception for the duration of treatment plus 7 months
             post-treatment completion; for all male patients, prior to treatment, advice should be
             sought for conserving sperm due to the chance of irreversible infertility as a
             consequence of treatment; genetic consultation is recommended if the patient wishes to
             have children after ending treatment. The investigator or a designated associate is
             requested to advise the patient how to achieve highly effective birth control.

               -  Highly effective (failure rate of less than 1% per year) contraception methods
                  include:

                    -  Combined (estrogen and progesterone containing: oral, intravaginal,
                       transdermal) and progesterone-only (oral, injectable, implantable) hormonal
                       contraception associated with inhibition of ovulation.

                    -  Intrauterine device (IUD) or intrauterine hormone-releasing system (IUS)

                    -  Bilateral tubal occlusion or vasectomized partner (provided that partner is
                       the sole sexual partner and has received medical assessment of the surgical
                       success)

                    -  Sexual abstinence (reliability to be evaluated in relation to the duration
                       of the clinical trial and the preferred and usual lifestyle of the patient)

               -  Male patients with a female partner of childbearing potential must use a condom
                  and ensure that an additional form of contraception is also used during treatment
                  plus 7 months post-treatment completion.

                    -  Note: a woman is considered WOCBP, i.e. fertile, following menarche and
                       until becoming postmenopausal unless permanently sterile; permanent
                       sterilization methods include but are not limited to hysterectomy, bilateral
                       salpingectomy and bilateral oophorectomy

               -  A postmenopausal state is defined as no menses for 12 months without an
                  alternative medical cause. A high follicle stimulating hormone (FSH) level in the
                  postmenopausal range may be used to confirm a postmenopausal state in women not
                  using hormonal contraception or hormonal replacement therapy. A man is considered
                  fertile after puberty unless permanently sterile by bilateral orchiectomy

          -  Absolute neutrophil count (ANC) >= 1500/mcL

          -  Platelets >= 100,000/mcL

          -  Hemoglobin >= 9 g/dL

               -  Patients must have not had a transfusion in the 2 weeks preceding this hemoglobin
                  (Hb) measurement

          -  Serum creatinine OR measured or calculated creatinine clearance: Serum creatinine
             clearance (CL) >= 60 mL/min or by 24-hour urine collection for determination of
             creatinine clearance

               -  Creatinine clearance should be calculated with Cockcroft-Gault formula
                  (Cockcroft-Gault 1976)

          -  Serum total bilirubin: Serum bilirubin =< 1.5 x institutional upper limit of normal
             (ULN). This will not apply to subject with confirmed Gilbert's syndrome (persistent or
             recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of
             hemolysis or hepatic pathology), who will be allowed only in consultation with their
             physician

          -  Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and
             alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]):
             AST/ALT=< 2.5 x institutional ULN in ALL patients regardless of presence or absence of
             liver metastases

          -  Albumin >= 2.5 mg/dL

          -  Ability to understand and the willingness to sign a written informed consent document

        Exclusion Criteria:

          -  Participation in another clinical study with an investigational product during the
             last 28 days or 5 half-lives prior to study day 1, whichever is shorter; concurrent
             enrollment in a non-interventional clinical study or the follow-up period of an
             interventional study is allowed

          -  Untreated central nervous system (CNS) metastatic disease, leptomeningeal disease, or
             cord compression; subjects with previously treated brain metastases may participate
             provided they are stable (without evidence of progression by imaging for at least six
             weeks prior to the first dose of trial treatment 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 trial treatment

          -  Evidence of uncontrolled, active infection, requiring parenteral anti-bacterial,
             anti-viral or anti-fungal therapy (washout: 7 days prior to cycle 1 day 1 [C1D1])

          -  Current or prior use of systemic immunosuppressive medication (except corticosteroids
             at physiological doses, not exceeding 10 mg prednisone-equivalent day) within 10 days
             before the first dose of study medication; intranasal, inhaled, topical, or local
             steroid injections are allowed; steroids as premedication for hypersensitivity
             reactions (i.e. CT scan premedication) are allowed

          -  Any major surgery within 4 weeks of study drug administration

          -  Concomitant second malignancies (except adequately treated squamous cell carcinoma
             [SCC] or basal cell carcinoma [BCC] skin cancers or in situ bladder, breast or
             cervical cancers) within the last 3 years prior to study entry

          -  Uncontrolled or significant cardiovascular disease, including but not limited to
             ongoing or active symptomatic congestive heart failure, uncontrolled hypertension,
             unstable angina pectoris, unstable cardiac arrhythmia

          -  National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE)
             version (v)5 >= grade (G)2 peripheral neuropathy (sensory or motor)

          -  Patients with corneal epitheliopathy and at the discretion of the ophthalmologist any
             other eye disorder

               -  Note: Low grades of superficial punctate keratitis, within the range seen in the
                  normal population, should not lead to the exclusion of the patient

          -  Active or prior documented inflammatory bowel disease (i.e. ulcerative colitis)

          -  Active or prior documented autoimmune disease within the past 2 years

               -  Note: subjects with vitiligo, Grave's disease, psoriasis not requiring systemic
                  treatment or hypothyroidism (i.e. following Hashimoto syndrome) stable on hormone
                  replacement are not excluded

          -  Recent history or current evidence of bleeding disorder (i.e. any CTCAE G >= 2
             hemorrhage/bleeding event within 28 days before the start of treatment)

          -  Active human immunodeficiency virus (HIV), hepatitis B or C infection; HIV-positive
             patients on antiretroviral therapy with undetectable viral load will not be excluded
             from the trial; subjects with treated hepatitis B or C with unquantifiable viral loads
             and no organ compromise are not excluded

          -  Any condition that, in the opinion of the investigator, would interfere with
             evaluation of study treatment or interpretation of patient safety or study results

          -  Pregnant women are excluded from this study because of the potential for teratogenic
             or abortifacient effects; because there is an unknown but potential risk for adverse
             events in nursing infants secondary to treatment of the mother, breastfeeding should
             be discontinued for at least 6 months after last dose of study drugs; these potential
             risks may also apply to other agents used in this study; should a patient become
             pregnant or suspect she is pregnant while she is participating in this study, the
             patient should inform the treating physician immediately
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum tolerated dose (MTD)
Time Frame:Up to 30-37 days post treatment
Safety Issue:
Description:This study will follow a 3+3 dose escalation design.

Secondary Outcome Measures

Measure:Biomarker analysis
Time Frame:Up to 100 days post treatment
Safety Issue:
Description:The analysis on proposed biomarkers is exploratory and hypothesis generating in nature. The key biomarker is CD8. CD8 after anetumab will be compared with CD8 after immunotherapy. Paired T-test will be carried out to identify changes in each biomarker between time points and mixed model will be used to study the trend in biomarkers over time when multiple measurements are available. The association between baseline biomarkers or change in biomarkers and clinical outcome PFS, toxicity and overall response will also be analyzed by Cox model or logistic model where appropriate. The results may be adjusted using Pocock method for multiplicity.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

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