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

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ClinicalTrials.gov Identifier: NCT03816358
Recruitment Status : Suspended (Other - Validation of Assay)
First Posted : January 25, 2019
Last Update Posted : April 17, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
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 Biological: Anetumab Ravtansine Drug: Gemcitabine Hydrochloride Biological: Ipilimumab Biological: Nivolumab Phase 1

  Show Detailed Description

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 64 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
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
Estimated Study Start Date : July 1, 2019
Estimated Primary Completion Date : April 30, 2021
Estimated Study Completion Date : April 30, 2021


Arm Intervention/treatment
Experimental: Arm I (anetumab ravtansine, nivolumab)
Patients 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.
Biological: Anetumab Ravtansine
Given IV
Other Name: BAY 94-9343

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Experimental: Arm II (anetumab ravtansine, nivolumab, ipilimumab)
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.
Biological: Anetumab Ravtansine
Given IV
Other Name: BAY 94-9343

Biological: Ipilimumab
Given IV
Other Names:
  • Anti-Cytotoxic T-Lymphocyte-Associated Antigen-4 Monoclonal Antibody
  • BMS-734016
  • MDX-010
  • MDX-CTLA4
  • Yervoy

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo

Experimental: Arm III (anetumab ravtansine, nivolumab, gemcitabine)
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.
Biological: Anetumab Ravtansine
Given IV
Other Name: BAY 94-9343

Drug: Gemcitabine Hydrochloride
Given IV
Other Names:
  • dFdCyd
  • Difluorodeoxycytidine Hydrochloride
  • Gemzar
  • LY-188011
  • LY188011

Biological: Nivolumab
Given IV
Other Names:
  • BMS-936558
  • MDX-1106
  • NIVO
  • ONO-4538
  • Opdivo




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) [ Time Frame: Up to 30-37 days post treatment ]
    This study will follow a 3+3 dose escalation design.


Secondary Outcome Measures :
  1. Biomarker analysis [ Time Frame: Up to 100 days post treatment ]
    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.



Information from the National Library of Medicine

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03816358


Locations
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Canada, Ontario
University Health Network Princess Margaret Cancer Center LAO
Toronto, Ontario, Canada, M5G 2M9
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Anna Spreafico University Health Network Princess Margaret Cancer Center LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03816358     History of Changes
Other Study ID Numbers: NCI-2019-00242
NCI-2019-00242 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PJC-026
10208 ( Other Identifier: University Health Network Princess Margaret Cancer Center LAO )
10208 ( Other Identifier: CTEP )
UM1CA186644 ( U.S. NIH Grant/Contract )
First Posted: January 25, 2019    Key Record Dates
Last Update Posted: April 17, 2019
Last Verified: January 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Yes
Plan Description: NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page
URL: https://grants.nih.gov/policy/sharing.htm

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

Additional relevant MeSH terms:
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Pancreatic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Endocrine Gland Neoplasms
Pancreatic Diseases
Adenocarcinoma
Carcinoma
Digestive System Diseases
Endocrine System Diseases
Gemcitabine
Nivolumab
Ipilimumab
Maytansine
Antibodies
Immunoconjugates
Antimetabolites, Antineoplastic
Antimetabolites
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Antiviral Agents
Anti-Infective Agents
Enzyme Inhibitors
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents, Immunological
Antineoplastic Agents, Phytogenic