J15222: A Clinical Trial of Pembrolizumab (MK-3475) Evaluating Predictive Biomarkers in Subjects with Advanced Solid Tumors (KEYNOTE 158)
Ana De jesus-acosta
Johns Hopkins Kimmel Cancer Center in Baltimore
#1:To evaluate the ORR to Pembrolizumab, based on RECIST 1.1 as assessed by independent central radiologic review, in biomarker-unselected subjects with any one of multiple types of advanced (metastatic and/or resectable) solid tumors.#2: To evaluate the ORR to Pembrolizumab, based on RECIST 1.1 as assessed by independent central radiologic review, in biomarker-selected subjects with any one of the multiple types of advanced (metastatic and/or resectable) solid tumors (Groups A-K). The primary biomarkers to be evaluated are (1) tumor expression of PD-L1 by IHC (Groups A-J), (2) tumor GEP by RNA analysis (Groups A-J), and (3) tumor MSI-H (Groups A-K).
Inclusion:1. Be willing and able to provide written informed consent/assent for the trial. The subject may also provide consent/assent for Future Biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.2. Be equal to 18 years of age on the day of signing informed consent.3. Have a histologically or cytologically-documented, advanced (metastatic and/or unresectable) solid tumor that is incurable and for which prior standard first-line treatment has failed. Patients must have progressed on or be intolerant to therapies that are known to provide clinical benefit. There is no limit to the number of prior treatment regimens.4. Have one of the following advanced (unresectable and/or metastatic) tumor types:(A) Anal Squamous Cell Carcinoma,(B) Biliary Adenocarcinoma (gallbladder or biliary tree (intrahepatic or extrahepatic cholangiocarcinoma) except Ampulla of Vater Cancers,(C) Neuroendocrine Tumors (well- and moderately-differentiated), of the lung, appendix, small intestine, colon, rectum, or pancreas,(D) Endometrial Carcinoma (sarcomas and mesenchymal tumors are excluded),(E) Cervical Squamous Cell Carcinoma,(F) Vulvar Squamous Cell Carcinoma,(G) Small Cell Lung Carcinoma,(H) Mesothelioma (Malignant Pleural Mesothelioma),(I) Thyroid Carcinoma (Papillary or Follicular Subtypes),(J) Salivary Gland Carcinoma (sarcomas and mesenchymal tumors are excluded) OR(K) Any other advanced solid tumor (except CRC), which is MSI-H.5. Have submitted an evaluable tissue sample for biomarker analysis from a tumorlesion not previously irradiated (exceptions may be considered after Sponsorconsultation). (See Procedure Manual for detailed instructions). The tumor tissue submitted for analysis must be from a single tumor tissue specimen and of sufficient quantity and quality to allow assessment of ALL required primary biomarkers.6. If enrollment in Groups A-J has moved to biomarker enrichment, have a tumor that is positive for one or more of the pre-specified primary biomarker(s), as assessed by the central laboratory. These enrichment biomarkers may be PD-L1 expression by IHC (at a percentage to be prespecified), a positive tumor RNA GEP score (at a prespecified cut-off), and/or tumor MSI-H.7.Have radiologically measurable disease based on RECIST 1.1. Independent central radiologic review must confirm the presence of radiologically measureable disease based on RECIST 1.1 for the subject to be eligible to participate in the trial (see Site Imaging Manual for detailed instructions). Tumor lesions situated in a previously irradiated area are considered measurable if progression has been demonstrated in such lesions.8. Have a performance status of 0 or 1 on the ECOG Performance Scale.9. Demonstrate adequate organ function10. Female subjects of childbearing potential must have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of trial medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required.11. Female subjects of childbearing potential (See Section 5.7.2) must be willing to use an adequate method of contraception, as outlined in Section 5.7.2. – Contraception,for the course of the study through 120 days after the last dose of trial medication.12. Male subjects of childbearing potential (See Section 5.7.2.) must agree to use an adequate method of contraception, as outlined in Section 5.7.2. – Contraception, for the course of the study through 120 days after the last dose of trial medication.Exclusion:1. Is currently participating and receiving study therapy or has participated in a study of an investigational agent and received study therapy or used an investigation device within 4 weeks of the first dose of treatment.2. Has a diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior to the first dose of trial treatment. The use of physiologic doses of corticosteroids may be approved after consultation with the Sponsor.3. Has an active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids orimmunosuppressive drugs). Replacement therapy (e.g., thyroxi ne, insulin, orphysiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency)is not considered a form of systemic treatment.4. Has had a prior anti-cancer monoclonal antibody (mAb) within 4 weeks prior to study Day 1 or who has not recovered (i.e., equal to Grade 1 or at baseline) from an AE due to mAbs administered more than 4 weeks earlier.5. Has had prior chemotherapy, targeted small molecule therapy, or radiation therapy within 2 weeks prior to study Day 1 or who has not recovered (i.e., equal to Grade 1 or at baseline) from an AE due to a previously administered agent.6.Has a known additional malignancy within 2 years prior to enrollment with theexception of curatively treated basal cell carcinoma of the skin, squamous cellcarcinoma of the skin, and/or curatively resected in situ cervical and/or in situ breast cancers.7.Has known active central nervous system (CNS) metastases and/or carcinomatousmeningitis. Subjects with previously treated brain metastases may participateprovided these brain metastases are stable (without evidence of progression byimaging over a period of at least 4 weeks and any neurologic symptoms have returned to baseline), they have no evidence of new or enlarging brain metastases (confirmed by imaging within 28 days of the first dose of trial treatment), and they are not using steroids for at least 7 days prior to trial treatment. This exception does not include carcinomatous meningitis which is excluded regardless of clinical stability.8. Has evidence of active non-infectious pneumonitis.9. Has an active infection requiring systemic therapy.10. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject’s participation for the full duration of the trial, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.11. Has known psychiatric or substance abuse disorders that would interfere withcooperation with the requirements of the trial.12. Is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 120 days after the last dose of trial treatment.13. Has previously participated in any other pembrolizumab (MK-3475) trial, or received prior therapy with an anti-PD-1, anti-PD-L1, anti-PD-L2, or any other immunemodulating mAb (including ipilimumab and any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways).14. Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).15. Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA [qualitative] is detected).16. Has received a live vaccine within 30 days of planned start of study therapy.
This is a non-randomized, multi-site, open-label trial of pembrolizumab (MK-3475) in subjects with multiple types of advanced (unresectable and/or metastatic) rare cancers to be conducted in conformance with Good Clinical Practices. The primary purpose of this trial is to assess the Objective Response Rate (ORR) to treatment with pembrolizumab (MK-3475)using Response Evaluation Criteria in Solid Tumors (RECIST), version 1.1 (RECIST 1.1), asdetermined by independent central radiologic review. This trial will also evaluate the efficacy of pembrolizumab in subgroups defined by each of three prespecified primary biomarkers.
03/05/2019 05:03 AM