Ensayos clínicos

Inclusion Criteria - Monotherapy:

Patients enrolling to SEA-CD40 monotherapy must meet the following inclusion criteria:

• Histologically confirmed advanced malignancy, defined as:
  • One of the following disease indications:
    • Metastatic or unresectable solid malignancy;
    • Lymphoma, either:
      • Classical Hodgkin lymphoma (HL);
      • Diffuse large B-cell lymphoma (DLBCL), as defined by the World Health Organization (WHO) criteria. Transformed DLBCL patients who have prior documentation of indolent disease are also eligible;
      • Indolent lymphoma, including follicular lymphoma (FL).
  • Relapsed, refractory, or progressive disease, specifically:
    • Solid tumors: Following at least 1 prior systemic therapy;
    • Classical HL: Following at least 2 prior systemic therapies in patients who are not candidates for autologous SCT, or following failure of autologous SCT. Patients who have not received autologous SCT must have refused or been deemed ineligible (e.g., due to age, co-morbid conditions);
    • DLBCL: Following at least 1 prior systemic therapy; patients must have also received intensive salvage therapy (defined as combination chemotherapy ± autologous SCT) unless they refused or were deemed ineligible;
    • Indolent lymphoma: Following at least 1 prior chemoimmunotherapy regimen that included an anti-CD20 monoclonal antibody and for which no other more appropriate treatment option exists as determined by the  investigator.
  • Representative baseline tumor tissue sample is available as follows:
    • New baseline biopsy of a tumor lesion not previously irradiated (preferred) or archived tumor tissue sample obtained prior to study enrollment (see Section 7.2);
    • If archived tissue is not available, a new biopsy of a tumor lesion not previously irradiated is required, unless the patient’s tumor is considered inaccessible or inappropriate for biopsy (in the opinion of the  investigator). Patients with tumors considered not accessible or appropriate for biopsy must be approved by the medical monitor for enrollment.
• In the dose-intensification arms of Part A and Part C, and in the disease-specific expansion cohort portions of the trial (Parts B, D, H, and K), patients must agree to baseline and on-treatment biopsy as scheduled, unless the patient’s tumor is  considered inaccessible or inappropriate for biopsy (in the opinion of the investigator). Patients with tumors considered not accessible or appropriate for biopsy must be approved by the medical monitor for enrollment. 
• Solid tumor monotherapy (both IV and SC administration): No further standard therapy is available for the patient’s advanced solid tumor at the time of enrollment.
• Measurable disease, defined as:
  • Solid tumors: At least 1 tumor lesion ≥10 mm in the longest diameter or a lymph node ≥15 mm in short-axis measurement assessed by computed tomography (CT) scan (RECIST v1.1). Lesions situated in a previously irradiated  area are considered measurable if progression has been demonstrated in such lesions. For dose levels at which single-patient cohorts are planned, measurable disease is not required;
  • Lymphomas: Fluorodeoxyglucose (FDG)-avid disease by positron emission tomography (PET) and measurable disease of ≥15 mm in the greatest transverse diameter by CT, as assessed by the site radiologist.
• Age ≥18 years.
• An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
  • See Appendix E for conversion of performance status using Karnofsky scales, if applicable.
• Completion of prior therapy within an acceptable timeframe before the first dose of study drug as follows:
  • Chemotherapy, small molecule inhibitors, and/or other investigational anticancer agents (excluding investigational monoclonal antibodies): 4 weeks;
  • Immune-checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, or anti-CTLA-4):  4 weeks (or 8 weeks if immuno-oncology doublet used as the prior line of therapy);
  • Other monoclonal antibodies, antibody-drug conjugates, or radioimmunoconjugates:  4 weeks (2 weeks with documented disease progression);
  • T-cell or other cell-based therapies: 12 weeks (or 2 weeks with documented disease progression);
  • Radiotherapy as follows:
    • Therapeutic: 2 weeks; must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis;
    • Palliative (≤2 weeks of radiotherapy to non-CNS disease): 1 week.
• Recovery to Grade 1 of any clinically significant toxicity attributed to prior anticancer therapy (excluding alopecia) prior to initiation of study drug administration.
• The following baseline laboratory parameters:
  • Absolute neutrophil count (ANC) ≥1500/μL;
  • Platelet count ≥100,000/μL;
  • Hemoglobin ≥8.0 g/dL;
  • Serum total bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for patients with Gilbert’s disease ;
  • Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 or ≤1.5 x ULN, using the Modification of Diet in Renal Disease (MDRD) study equation as applicable;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN (≤5 x ULN if there is evidence of hepatic involvement by malignant disease).
• Female patients; for those of childbearing potential as defined in Section 4.3, the following stipulations apply:
  • Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 7 days prior to the first dose of SEA-CD40. Females with false positive results and documented verification that the patient is not pregnant are eligible for participation;
  • Must agree not to try to become pregnant during the study and for at least 6 months after the last dose of study drug administration ;
  • Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 6 months after the last dose of study drug administration
• Heterosexually active females of childbearing potential and males who can father children that have partners of childbearing potential must consistently use 2 highly effective methods of birth control (as defined in Appendix L) starting at the time of informed consent and continuing throughout the study and for at least 6 months after the last dose of study drug administration.
• Patients must provide written informed consent.
• Male patient must agree not to donate sperm starting at the time of informed consent and continuing throughout the study period and for at least 6 months after the last dose of study drug administration.

Exclusion Criteria - Monotherapy:

• Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III–IV (see Appendix F) within 6 months prior to their first dose of SEA-CD40.
• Any serious health condition, which, in the opinion of the investigator, would place the patient at undue risk from the study, including uncontrolled hypertension and/or diabetes, clinically significant pulmonary disease (e.g., interstitial lung disease; or chronic obstructive pulmonary disease requiring hospitalization within 3 months) or neurological disorder (e.g., seizure disorder active within 3 months).
• Recent or ongoing serious infection, including:
  • Any active Grade 3 or higher (per the NCI CTCAE, version 4.03) viral, bacterial, or fungal infection within 2 weeks of the first dose of study drug. Routine antimicrobial prophylaxis is permitted;
  • Known seropositivity for or active infection by human immunodeficiency virus (HIV);
  • Known positive for hepatitis B by surface antigen expression, or any other positive test for hepatitis B virus indicating acute or chronic infection;
  • Known active hepatitis C infection (positive by serology and confirmed by polymerase chain reaction) or on antiviral therapy for hepatitis C within 6 months of first dose of study drug.
• Autoimmune or auto-inflammatory ocular disease, such as uveitis, iritis, scleritis, or optic neuritis, active within the previous 6 months, which may be exacerbated by the known mechanism of action of SEA-CD40.
• Any known or suspected active organ-threatening autoimmune disease, such as inflammatory bowel disease, autoimmune hepatitis, lupus, or pneumonitis.
• Women who are breastfeeding.
• Active central nervous system (CNS) tumor or metastases. Patients are eligible if CNS metastases are adequately treated and patients are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 4 weeks prior to enrollment.
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (with corticosteroids at >10 mg/day prednisone or equivalent) or any other form of immunosuppressive therapy within 1 week prior to the first dose of study drug.
• Known hypersensitivity to any excipient contained in the drug formulations of the study treatment(s).
• History of another invasive malignancy that has not been in remission for at least 2 years.
• The following are exempt from the 2-year limit: nonmelanoma skin cancer, curatively treated localized prostate cancer, indolent localized prostate cancer under observation, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP smear.
• Patients with lymphomas (Parts C, D, J, and K): Prior allogeneic SCT.

Inclusion Criteria - Combination Therapy (Parts E and F):

Patients enrolling in combination therapy must meet the following inclusion criteria.

• Histologically or cytologically confirmed advanced or metastatic solid malignancy; specifically:
  • In Part E (dose escalation): Must be a malignancy for which pembrolizumab is approved. As of December 2017, these include:
  • Advanced/metastatic or unresectable melanoma;
  • Metastatic non-small cell lung cancer (NSCLC) where tumors have high PD-L1 expression, defined as:
    • Tumor proportion score [TPS] ≥50% as determined by an FDA-approved test;
    • With no epidermal growth factor receptor (EGFR) or anaplastic lymphoma kinase (ALK) genomic tumor aberrations;
    • With no prior systemic chemotherapy treatment for metastatic NSCLC.
  • Metastatic NSCLC whose tumors express PD-L1 (TPS ≥1% as determined by an FDA-approved test), with disease progression on or after platinum-containing chemotherapy. Patient with EGFR or ALK genomic tumor aberrations should have disease progression on FDA-approved therapy for these aberrations prior to receiving pembrolizumab.
  • Recurrent or metastatic head and neck squamous cell carcinoma (HNSCC) with disease progression on or after platinum-containing chemotherapy.
  • Locally advanced or metastatic urothelial carcinoma in patients who have disease progression during or following platinum-containing chemotherapy or within 12 months of neoadjuvant or adjuvant treatment with platinum-containing chemotherapy.
  • Unresectable or metastatic high level microsatellite instability (MSI-H) or mismatch repair deficient (dMMR) solid tumors that have progressed following prior treatment and who have no satisfactory alternative treatment options, or colorectal cancer that has progressed following treatment with a fluoropyrimidine, oxaliplatin, and irinotecan.
  • Recurrent locally advanced or metastatic gastric or gastroesophageal junction adenocarcinoma whose tumors express PD-L1, defined as:
    • Combined positive score [CPS] ≥1 as determined by an FDA-approved test;
    • With disease progression on or after 2 or more prior lines of therapy including fluoropyrimidine- and platinum-containing chemotherapy and if appropriate, human epidermal growth factor receptor 2 (HER2)/neu-targeted therapy.
  • As solid tumor indications are added to the approved US package insert for pembrolizumab, patients with these tumors may be eligible for participation in the combination therapy dose-escalation portion of the trial upon SMC approval.
  • In Part F (disease-specific expansion cohorts), either:
    • Malignancies for which pembrolizumab treatment is approved, as listed in 1a;
    • Other advanced solid tumor indication as defined by the SMC, where the patient’s disease has progressed after treatment with at least 1 prior appropriate available therapy for metastatic disease that is known to confer clinical benefit, or is intolerant to treatment.
  • Representative baseline tumor tissue sample is available as follows:
    • New baseline biopsy of a tumor lesion not previously irradiated (preferred) or archived tumor tissue sample obtained prior to study enrollment (see Section 7.2);
    • If archived tissue is not available, a new biopsy of a tumor lesion not previously irradiated is required, unless the patient’s tumor is considered inaccessible or inappropriate for biopsy (in the opinion of the investigator). Patients with tumors considered not accessible or appropriate for biopsy must be approved by the medical monitor for enrollment.
• In Part F, patients must agree to baseline and on-treatment biopsies as scheduled, unless the patient’s tumor is considered inaccessible or inappropriate for biopsy (in the opinion of the investigator). Patients with tumors considered not accessible or appropriate for biopsy must be approved by the medical monitor for enrollment.
• In Part F, patients previously exposed to PD-L1 therapy must have progressed on treatment with an anti-PD1/L1 monoclonal antibody (mAb) administered either as monotherapy, or in combination with other checkpoint inhibitors or other therapies. PD-1 treatment progression is defined by meeting all of the following criteria:
  • Has received at least 2 doses of an approved anti-PD-1/L1 mAb;
  • Has demonstrated disease progression after PD-1/L1 as defined by RECIST v1.1. The initial evidence of disease progression (PD) is to be confirmed by a second assessment no less than 4 weeks from the date of the first  documented PD, in the absence of rapid clinical progression (Seymour 2017). This determination is made by the investigator. Once PD is confirmed, the initial date of PD documentation will be considered the date of disease progression;
  • Progressive disease has been documented within 12 weeks from the last dose of anti-PD-1/L1 mAb.
• Measurable disease per RECIST v1.1 with at least 1 tumor lesion ≥10 mm in the longest diameter or a lymph node ≥15 mm in short-axis measurement assessed by computed tomography (CT) scan (RECIST v1.1). Lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions. For dose levels at which single-patient cohorts are planned, measurable disease is not required.
• Age ≥18 years.
• An Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1.
• Completion of prior therapy within an acceptable timeframe before the first dose of study drug as follows:
  • Chemotherapy, small molecule inhibitors, and/or other investigational anticancer agents (excluding investigational monoclonal antibodies): 4 weeks;
  • Immune-checkpoint inhibitors (e.g., anti-PD-1, anti-PD-L1, or anti-CTLA-4): 4 weeks (or 8 weeks if immuno-oncology doublet used as the prior line of therapy);
  • Other monoclonal antibodies, antibody-drug conjugates, or radioimmunoconjugates: 4 weeks (2 weeks with documented disease progression);
  • T-cell or other cell-based therapies: 12 weeks (or 2 weeks with documented disease progression);
  • Radiotherapy as follows:
    • Therapeutic: 2 weeks; must have recovered from all radiation-related toxicities, not require corticosteroids, and not have had radiation pneumonitis;
    • Palliative (≤2 weeks of radiotherapy to non-CNS disease): 1 week.
• Recovery to Grade 1 of any clinically significant toxicity attributed to prior anticancer therapy (excluding alopecia) prior to initiation of study drug administration.
• The following baseline laboratory parameters:
  • Absolute neutrophil count (ANC) ≥1500/μL;
  • Platelet count ≥100,000/μL;
  • Hemoglobin ≥8.0 /dL;
  • Serum total bilirubin ≤1.5 x upper limit of normal (ULN) or ≤3 x ULN for patients with Gilbert’s disease;
  • Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 or ≤1.5 x ULN, using the Modification of Diet in Renal Disease (MDRD) study equation as applicable;
  • Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x ULN (≤5 x ULN if there is evidence of hepatic involvement by malignant disease);
  • Coagulation:
    • International normalized ratio (INR) or prothrombin time (PT) ≤1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or activated partial omboplastin time (aPTT) is within therapeutic range of intended use of anticoagulants;
    • Activated partial thromboplastin time (aPTT) ≤1.5 x ULN unless patient is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants.
• Female patients; for those of childbearing potential as defined in Section 4.3, the following stipulations apply:
  • Must have a negative serum or urine pregnancy test (minimum sensitivity 25 mIU/mL or equivalent units of beta human chorionic gonadotropin [β-hCG]) result within 7 days prior to the first dose of SEA-CD40. Females with false positive results and documented verification that the patient is not pregnant are eligible for participation;
  • Must agree not to try to become pregnant during the study and for at least 6 months after the last dose of study drug administration;
  • Must agree not to breastfeed or donate ova, starting at time of informed consent and continuing through 6 months after the last dose of study drug administration.
• Heterosexually active females of childbearing potential and males who can father children that have partners of childbearing potential must consistently use 2 highly effective methods of birth control (as defined in Appendix L) starting at the time of informed consent and continuing throughout the study and for at least 6 months after the last dose of study drug administration.
• Patients must provide written informed consent.
• Male patient must agree not to donate sperm starting at the time of informed consent and continuing throughout the study period and for at least 6 months after the last dose of study drug administration.

• Exclusion Criteria - Combination Therapy:

• Documented history of a cerebral vascular event (stroke or transient ischemic attack), unstable angina, myocardial infarction, or cardiac symptoms consistent with New York Heart Association (NYHA) Class III–IV (see Appendix F) within 6 months prior to their first dose of SEA-CD40.
• Any serious health condition, which, in the opinion of the investigator, would place the patient at undue risk from the study, including uncontrolled hypertension and/or diabetes, clinically significant pulmonary disease (e.g., interstitial lung disease; or chronic obstructive pulmonary disease requiring hospitalization within 3 months) or neurological disorder (e.g., seizure disorder active within 3 months).
• Recent or ongoing serious infection, including:
  • Any active Grade 3 or higher (per the NCI CTCAE, version 4.03) viral, bacterial, or fungal infection requiring systemic therapy within 2 weeks of the first dose of study drug. Routine antimicrobial prophylaxis is permitted;
  • Known seropositivity for or active infection by human immunodeficiency virus (HIV);
  • Known positive for hepatitis B by surface antigen expression, or any other positive test for hepatitis B virus indicating acute or chronic infection;
  • Known active hepatitis C infection (positive by serology and confirmed by polymerase chain reaction) or on antiviral therapy for hepatitis C within 6 months of first dose of study drug.
• Autoimmune or auto-inflammatory ocular disease, such as uveitis, iritis, scleritis, or optic neuritis, active within the previous 6 months, which may be exacerbated by the known mechanism of action of SEA-CD40.
• Any known or suspected active organ-threatening autoimmune disease, such as inflammatory bowel disease, autoimmune hepatitis, lupus, or pneumonitis (current pneumonitis or history of non-infectious pneumonitis that required steroids).
• Women who are breastfeeding.
• Active central nervous system (CNS) tumor or metastases. Patients are eligible if CNS metastases are adequately treated and patients are neurologically returned to baseline (except for residual signs or symptoms related to the CNS treatment) for at least 4 weeks prior to enrollment.
• Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (with corticosteroids at >10 mg/day prednisone or equivalent) or any other form of immunosuppressive therapy within 1 week prior to the first dose of study drug.
• Known hypersensitivity to any excipient contained in the drug formulations of the study treatment(s).
• History of another invasive malignancy that has not been in remission for at least 2 years.
• The following are exempt from the 2-year limit: nonmelanoma skin cancer, curatively treated localized prostate cancer, indolent localized prostate cancer under observation, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on PAP smear.
  • Administrative note: This criterion is a placeholder and is included for administrative numbering purposes only. It does not contain an exclusion criterion that patients enrolling to combination therapy Parts E and F must meet.
• History of severe immune-mediated adverse reactions to pembrolizumab.
• Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE).
• Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include but are not limited to, the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
• Has severe hypersensitivity (≥ Grade 3) to pembrolizumab and/or any of its excipients. 
• Active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs).  Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment and is allowed.
• History or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient’s participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the investigator.
• Known psychiatric or substance abuse disorders that would interfere with cooperating with the requirements of the study.