A Phase 1/2 Dose Escalation and Cohort Expansion Study of the Safety and Tolerability of Urelumab Administered in Combination with Nivolumab in Advanced/Metastatic Solid Tumors and B Cell Non-Hodgkins Lymphoma
You are being asked to take part in this study because you have advanced solid tumors, metastatic (has spread) B-cell non-Hodgkins lymphoma (B-cell NHL), melanoma, non-small cell lung cancer (NSCLC), head and neck squamous cell carcinoma (SCCHN), diffuse large B-cell lymphoma (DLBCL) and the disease has gotten worse after receiving the study drug on the main part of this study. If you agree, and if you are still eligible, you will continue to receive your assigned study drugs, even though the disease has appeared to have gotten worse. This is because the study drug may be working even though the tumor(s) got larger. However, there are risks of continuing to receive the study drugs because the disease may actually be getting worse. You are still at risk for side effects due to nivolumab and urelumab. This could also delay starting other treatments. The disease may get worse to the point that you are no longer able to receive other treatments. There are also risks from the additional tests that may be performed, such as biopsies and blood draws. You and the study doctor will discuss this, and if you agree, you will sign this consent and continue taking nivolumab and urelumab. You will continue to follow the study visits as described in the informed consent form you signed before starting the study. You will also continue to receive the study drug as described. You will be allowed to continue treatment with nivolumab and urelumab after the tumor grows, as long as: The study doctor thinks that you will benefit from continued treatment The tumor and disease does not quickly grow or get worse The symptoms you may be having from the disease are stable You can tolerate nivolumab and urelumab Your continued treatment with nivolumab and urelumab will not delay or stop an immediate medical treatment for the side effects due to the tumor growing You may continue taking the study drug for as long as the study doctor thinks it is in your best interest.
Disease Group: Genitourinary,Head And Neck,Lung,Lymphoma,Melanoma
Treatment Agent: BMS-663513,Nivolumab
Treatment Location: Both at MDACC & and Other Sites
Primary Objective To assess the safety and tolerability of urelumab given in combination with nivolumab and to identify dose limiting toxicities (DLTs) and the maximally tolerated dose (MTD) of the combination, in subjects with advanced (metastatic and/or resectable) solid tumors and B cell lymphomas. Secondary Objectives The secondary objectives are as follows: To assess the preliminary anti-tumor activity of the combination of urelumab and nivolumab in subjects with advanced solid tumors and B cell lymphomas. To characterize the pharmacokinetics (PK) of urelemab and nivolumab when co-administered. To monitor immunogenicity of urelemab and nivolumab administered as combination therapy. Exploratory Objectives The exploratory objectives are as follows: To assess the pharmacodynamic effects of urelumab as a function of exposure when given in combination with nivolumab in peripheral blood and tumor tissue. To explore potential associations between biomarker measures and anti-tumor activity. To assess the overall survival (OS) following the start of therapy with the combination of urelumab and nivolumab.
IRB Review and Approval Date: 01/26/2015
Recruitment Status: Open
Projected Accrual: 260
1) Signed Written Informed Consent: The subject must sign the informed
consent form prior to the performance of any study related procedures
that are not considered part of standard of care.
2) Target Population: a.) Subjects must have histological or cytologic confirmation of a malignancy that is advanced (metastatic and/or resectable): i) Dose Escalation: (1) All solid tumor and B-cell NHL histologies will be permitted during dose escalation, except for subjects with primary CNS tumors, CNS lymphoma or with CNS metastasis as the only site of active disease. (2) Subjects must have received and then progressed, or been intolerant to, at least one standard treatment regimen in the advanced metastatic setting, if such therapy exists. Subjects who refuse or are ineligible for standard therapy will be allowed to enroll provided their refusal/ineligibility is documented in medical records.
3) Target Population: ii) Cohort Expansion (1). The following four tumor types will be permitted during cohort expansion. a. Non Small Cell Lung Cancer (NSCLC) i. Must have recurrent or progressive disease during or after platinum doublet-based chemotherapy for advanced or metastatic disease OR must have recurred or progressive disease within six months after completing platinum-based chemotherapy for local disease. ii) Subjects with non-squamous histology must have known EGFR and ALK status. iii. Subjects with an activating EGFR mutation must have received an EGFR tyrosine kinase inhibitor. iv. Subjects with an ALK translocation must have received an ALK inhibitor. b. Melanoma (MEL) i. Not applicable. ii. Subjects must have known BRAF V600 mutation status or consent to BRAF V600 mutation testing per local institutional standards during the Screening Period.
4) Continued from inclusion criteria # 3 iii. Histologically confirmed unresectable Stage 3 or Stage 4 melanoma as per American Joint Committee on Cancer (AJCC) staging system.Treatment naive subjects (ie, no prior systemic anticancer therapy for unresectable or metastatic melanoma). 1. Note: Prior adjuvant or neoadjuvant melanoma therapy is permitted if it wascompleted at least 4 weeks or 5 half-life times (whichever is shorter) prior to randomization and all related adverse events have either returned to baseline or stabilized.
5) Population: ii) Cohort Expansion c. Head and Neck Squamous Cell Carcinoma (SCCHN) i.) Histologically confirmed incurable locally advanced, recurrent or metastatic SCCHN (oral cavity, pharynx, larynx), stage III/IV and not amenable to local therapy with curative intent (surgery or radiation therapy with or without chemotherapy). ii) Confirmation of tumor HPV status: Prior testing results are acceptable if known. If tumor HPV status is unknown, subjects must consent to allow their submitted archived tumor tissue sample in the form of block or unstained slides to be tested for confirmation of tumor HPV status. iii. Tumor progression or recurrence within 6 months of last dose of platinum therapy in the adjuvant (ie, with radiation after surgery), primary (ie, with radiation), recurrent, or metastatic setting.
6) Continued from inclusion criterion # 4: Clinical progression after platinum therapy is an allowable event for entry and is defined as progression of a lesion at least 10 mm in size that is amenable to caliper measurments (eg, superficial skin lesion as per RECIST 1.1) or a lesion that has been visualized and photographically recorded with measurements and shown to have progressed.
7) Continued from inclusion criterion #4: iv. Prior curative radiation therapy must have been completed at least 4 weeks prior to study drug administration. Prior focal palliative radiotherapy must have been completed at least 2 weeks before study drug administration. d. Tumor Biopsy confirmation of relapsed or refractory DLBCL, or transformed lymphoma (TL), prior to the initiation of study drug. i. TL is limited to DLBCL. Subjects with Grade 3b follicular lymphoma are excluded. ii. DLBCL or TL should be pathologically confirmed by standard immunohistochemical or flow cytometric techniques. iii. Documentation of the above should be present in the subject’s medical record. iv. Prior treatment as defined below; 1. Subjects with relapsed DLBCL or TL after high-dose conditioning chemotherapy and ASCT, or
8) Continued from inclusion cirterion #4: Subjects with relapsed or refractory DLBCL or TL after at least 1 prior multi-agent chemotherapy regimen if ASCT ineligible. Ineligibility for ASCT will be determined using local institutional criteria. v. Measurable disease: Subjects must have at least one lesion that is > 15 mm (1.5 cm) in the longest diameter on cross-sectional imaging and measureable in two perpendicular dimensions per computed tomography (spiral CT) or MRI. e. Non Small Cell Lung Cancer (NSCLC).Subjects with progressive or recurrent disease per RECIST 1.1 during or after anti-PD-1 or anti-PD-L1 therapy i. Must have received platinum based chemotherapy for advanced or metastatic disease or locally advanced disease ii. A minimum of 5 subjects in Part 1 of Cohort Expansion should have squamous histology iii. Subjects with non squamous histology must have known EGFR and ALK status. iv. Subjects with an activating EGFR mutation must have received an EGFR tyrosine kinase inhibitor.
9) Continued from inclusion criterion #4 v. Subjects with an ALK translocation must have received an ALK inhibitor. vi. Must have received anti-PD-1/anti-PD-L1 treatment as most recent therapy and have progressed during or after therapy. vii. The last dose of prior anti-PD-1/anti-PD-L1 treatment >/= 28 days from initiation of study therapy. viii. No more than 25% of NSCLC subjects (5 during stage 1 and 5 during stage 2 of cohort expansion) will be enrolled with primary refractory disease (ie, a BOR of PD per RECIST v1.1). The remaining subjects in the cohort will be subjects with relapsed disease (ie, SD, PR or CR but progressing on therapy). f. Follicular Lymphoma (FL) i. Tumor biopsy confirmation of relapsed or refractory FL must be obtained prior to the initiation of study drug. Grade 1, 2, or 3a FL without pathologic evidence of transformation. FL should be pathologically confirmed by standard immunohistochemical or flow cytometric techniques.
10) Continued from inclusion criterion #4: Documentation of the above should be present in the subject’s medical record.Treatment of FL consisting of >/= 2 prior treatment lines; each of the 2 prior treatment lines must include CD20 antibody and/or an alkylating agent (eg, bendamustine, cyclophosphamide, ifosfamide, melphalan, chlorambucil, busulfan, nitrosoureas). At least one of the prior treatment lines must include rituximab. NOTE: Separate lines of therapy are defined as 2 regimens separated by disease progression, relapsed disease, or refractory disease. ii. Definition of Relapsed FL 1. The appearance of new lesions > 6 months after obtaining a CR 2. An increase >/= 50% in the size of previously involved sites > 6 months after completing planned therapy. iii. Definition of Refractory FL 1. < 50% decrease in lesion size after planned therapy. 2. The appearance of new lesions during therapy or < 6 months after completion of planned therapy.
Criteria truncated, please contact Prinicipal Investigator's office for full criteria
1) Target Disease Exceptions a) Subjects with known or suspected central
nervous system (CNS) metastases or with the CNS as the only site of
disease are excluded. Subjects with CNS lymphoma are excluded. However,
subjects with controlled brain metastases will be allowed to enroll.
Controlled brain metastases are defined as no radiographic progression
for at least 4 weeks following radiation and/or surgical treatment (or 4
weeks of observation if no intervention is clinically indicated), and
off of steroids for at least 2 weeks, and no new or progressive
neurological signs and symptoms. Please note: for SCCHN subjects with
direct extension of tumor through the base of skull will not be excluded
as they are considered distinct from hematogenously spread parenchymal
2) Continuation of exclusion criterion #1: b) Ocular melanoma c) Participation in any prior clinical study with ipilimumab, or with nivolumab including subjects in comparator arms, in which overall survival is listed as the primary or coprimary endpoint and which has not completed analysis based on the primary endpoint. Exception:I-O experienced NSCLC and melanoma cohort (prior antibody therapy of anti-CTLA-4 and/or anti-PD-1 or anti-PDL-1). d) Subjects who have received nivolumab are not eligible to be enrolled with the exception for those NSCLC and MEL subjects enrolling in the expansion cohorts where prior anti-PD-1 or anti-PD-L1 therapies are specifically required.
3) Medical History and Concurrent Diseases a) Subjects with a prior malignancy are excluded, except adequately treated basal cell or squamous cell skin cancer, localized prostate cancer, carcinoma in situ of the cervix, or in situ ductal or lobular carcinoma of the breast. Subjects with other second malignancies diagnosed more than 2 years ago who have received therapy with curative intent with no evidence of disease during the interval who are considered by the investigator to present a low risk for recurrence will be eligible. b) Prior organ allograft or allogeneic bone marrow transplantation.
4) Continuation of exclusion criterion #3 c) Subjects with active, known or suspected autoimmune disease. Subjects with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune condition only requiring hormone replacement, euthyroid patients with a history of Grave’s disease (subjects with suspected autoimmune thyroid disorders must be negative for thyroglobulin and thyroid peroxidase antibodies and thyroid stimulating immunoglobulin prior to randomization), psoriasis not requiring systemic treatment, or conditions not expected to recur are permitted to enroll.
5) Continuation of exclusion criterion #3: d) A known or underlying medical condition that, in the opinion of the investigator or sponsor, could make the administration of study drug hazardous to the subjects, or could adversely affect the ability of the subject to comply with or tolerate the study. e) Uncontrolled or significant cardiovascular disease including, but not limited to any of the following: i) myocardial infarction or stroke/TIA within the past 6 months ii) uncontrolled angina within the past 3 months iii) any history of clinically significant arrhythmias (such as ventricular tachycardia, ventricular fibrillation or torsades de pointes) iv) QTc prolongation > 480 msec v) history of other clinically significant heart disease (ie, cardiomyopathy, congestive heart failure with NYHA functional classification III-IV, pericarditis, significant pericardial effusion) vi) requirement for daily supplemental oxygen therapy
6) Continuation of exclusion criterion #3: f) History of any chronic hepatitis as evidenced by: i) Positive test for hepatitis B surface antigen (HBsAg) and/or hepatitis B core antibody ii) Positive test for qualitative hepatitis C viral load (by PCR) Note: History of resolved hepatitis A virus infection is not an exclusion criterion. iii) History of alcoholic or non-alcoholic steatohepatitis (NASH), auto-immune hepatitis, or previous grade 3-4 drug-related hepatitis) or any form chronic liver disease will be excluded. g) Evidence of active infection </= 7 days prior to initiation of study drug therapy (does not apply to viral infections that are presumed to be associated with the underlying tumor type required for study entry).
7) Continuation of exclusion criterion #3: h) Evidence or history of active or latent tuberculosis infection including PPD recently converted to positive; chest x-ray with evidence of infectious infiltrate; recent unexplained changes in fever/chill patterns.i) Any significant acute or chronic medical illness. j) Any major surgery within 4 weeks of study drug administration. k) Subjects who are unable to undergo venipuncture and/or to tolerate venous access. l) Known current drug or alcohol abuse m) Any other sound medical, psychiatric and/or social reason as determined by the investigator.
8) Prohibited Prior Treatments and/or Therapies a) Prior therapy with immune checkpoint inhibitors (ie, anti-PD-1, anti-PD-L1, anti-LAG-3); immune co-stimulatory molecules (ie, anti-CD137, anti-OX40, anti-GITR); anti-cancer vaccines (Provenge, MAGE-3); or other immune modulating monoclonal antibodies. Prior anti-CTLA4, is permitted. Prior anti-PD-1/anti-PD-L1 therapy is permitted for the NSCLC cohort described in Protocol inclusion criteria 2(a)(ii)(1)(e) above. b) Subject who have received prior anti-CTLA4 therapy: i) Prior anti-CTLA4 therapy within 100 days from the first day of study therapy. ii) Subjects who have received prior anti-CTLA4 blockade and experienced the following immune-mediated adverse events:(1).Grade 3 or > pneumonitis, hepatitis, colitis, ocular events; (2).Any CNS event regardless of severity; (3) Any immune-mediated adverse event requiring additional immunosuppresive therapy beyond steroids for management.
9) Continuation of exclusion criterion #8: c) Any anti-cancer therapy (eg, chemotherapy, biologics, vaccines, radiotherapy, or hormonal treatment) including investigational drugs within 4 weeks prior to the first dose of study drug administration, with the exception of GnRH agonist therapy for subjects with prostate cancer. Prior palliative or targeted radiotherapy must have been completed at least 2 weeks prior to the first dose of study drug. d) Use of non-oncology vaccines containing live virus for prevention of infectious diseases within 4 weeks prior to study drug. The use of the inactivated seasonal influenza vaccine (Fluzone®) is allowed. e) Use of growth factors, including, but not limited to, granulocyte-colony stimulating factor (G-CSF), granulocyte macrophage-colony stimulating factor (GM-CSF) or erythropoietin within 4 weeks prior to the first dose of study drug and use of G-CSF within 2 weeks in DLBCL patients.
Criteria truncated, please contact Prinicipal Investigator's office for full criteria
Information and next steps
Genitourinary,Head And Neck,Lung,Lymphoma,Melanoma
Phase I/Phase II
Thoracic and Head and Neck Med
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