All Drugs and Chemicals

Immunomodulating Agents

Gamma-camera imaging

Low-risk biopsy

Patients undergoing immunotherapy for advanced cancer under IRB-approved protocols, who are to receive immune cells in adoptive transfer, will have less than or equal to 50% of those cells labeled with In-111-oxine and administered along with the remainder of their unlabeled cells. They will then undergo gamma-camera imaging over the next 0-7 days and blood samples and tumor sites which are accessible with minimal surgery (low-risk biopsy) may be sampled in some patients for enumeration of radiolabeled cells. End-points will be tumor and normal organ imaging and the amount of In-111 per gram of tissue in biopsies or per ml. of blood.

Trafficking of Indium-III-Labeled Cultured Immune Cells in Patients Undergoing Immunotherapy for Advanced Cancer

Trafficking of Indium-111-Labeled Cultured Immune Cells in Patients Undergoing Immunotherapy for Advanced Cancer

National Cancer Institute (NCI)

Symptoms and General Pathology

All Conditions

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

Death

Carcinoma

Carcinoma, Non-Small-Cell Lung

Lung Neoplasms

Carcinoma, Bronchogenic

Bronchial Neoplasms

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Antineoplastic Agents

Pembrolizumab

Male and female participants with histologically-confirmed diagnosis of squamous or nonsquamous NSCLC will be screened for participation in 1 of 4 pembrolizumab substudies.

Participants will undergo tumor imaging using either a magnetic resonance imaging (MRI) scan or a computed tomography (CT) scan.

Tumor Imaging

Participants without archival tumor tissue samples will undergo tumor tissue collection for newly obtained tumor tissue.

Tumor Tissue Collection

Participants will have blood samples drawn for analysis of:

* genetics
* ribonucleic acid (RNA)
* serum biomarker
* plasma biomarker
* circulating tumor DNA (ctDNA)

Blood Sample Collection

Toll Free Number

Study Coordinator

Medical Director

This study is referred to as the "umbrella master protocol" for pembrolizumab (MK-3475) in the treatment of non-small cell lung cancer (NSCLC). This pembrolizumab NSCLC umbrella master protocol uses a platform design and consists of this master screening study and three substudies. Each substudy will enroll a different population of NSCLC participants.

The goal of this umbrella master protocol is to screen potential participants with NSCLC for enrollment into 1 of 4 substudies. Participants must first enroll in this pembrolizumab master protocol study and undergo screening for NSCLC that will be used to assign them to participation in 1 of 4 pembrolizumab substudies.

The following 4 pembrolizumab substudies will evaluate the efficacy of different investigational agents in combination with pembrolizumab given in sequence or in combination with pembrolizumab PLUS chemotherapy:

* KEYMAKER-U01 Substudy 1: A Phase 2, Umbrella Study with Rolling Arms of Investigational Agents with Pembrolizumab in Combination with Chemotherapy in Treatment-Naïve Patients with Advanced Non-small Cell Lung Cancer (NSCLC) (MK-3475-01A) - NCT04165070
* KEYMAKER-U01 Substudy 2: A Phase 2, Umbrella Study with Rolling Arms of Investigational Agents in Combination with Pembrolizumab in Treatment Naïve Patients with PD-L1 Positive Advanced Non-small Cell Lung Cancer (NSCLC) (MK-3475-01B) - NCT04165083
* KEYMAKER-U01 Substudy 3: A Phase 2, Umbrella Study with Rolling Arms of Investigational Agents in Combination with Pembrolizumab in Patients with Advanced Non-small Cell Lung Cancer (NSCLC) Previously Treated with anti-PD-(L)1 Therapy (MK-3475-01C) - NCT04165096
* KEYMAKER-U01 Substudy 01E: A Phase 2 Umbrella Study With Rolling Arms of Investigational Agents With or Without Chemotherapy in Combination With Pembrolizumab in Treatment of Participants With Newly Diagnosed Resectable Stages II-IIIB (N2) Non-small Cell Lung Cancer (NSCLC) (MK-3475-01E) - NCT number pending

To identify novel biomarkers, biospecimens (i.e., blood components, tumor material) will be collected to support analyses of cellular components (eg, protein, DNA, RNA, metabolites) and other circulating molecules.

Investigations may include but are not limited to:

Germline (blood) genetic analyses (e.g. single nucleotide polymorphism \[SNP\] analyses, whole exome sequencing, whole genome sequencing)

KEYMAKER-U01 Umbrella Master Study: Studies of Investigational Agents With Either Pembrolizumab (MK-3475) Alone or With Pembrolizumab PLUS Chemotherapy in Participants With Advanced Non-small Cell Lung Cancer (NSCLC) (MK-3475-U01/KEYMAKER-U01)

KEYMAKER-U01 Master Study: A Phase 2, Umbrella Study With Rolling Arms of Investigational Agents With Either Pembrolizumab in Combination With Chemotherapy or With Pembrolizumab Alone in Patients With Advanced Non-small Cell Lung Cancer (NSCLC)

http://engagezone.msd.com/doc/ProcedureAccessClinicalTrialData.pdf

Participants' tumors will be evaluated for their PD-L1 tumor expression level using archival tumor tissue samples or newly obtained tumor tissue. The percentage of participants who have a Tumor Proportion Score (TPS) \<1% vs. a TPS =1% will be presented.

Participants' tumors will be evaluated for their tumor histology status as being either squamous vs. nonsquamous NSCLC using archival or newly obtained tumor tissue samples. The percentage of participants who have squamous vs. nonsquamous NSCLC will be presented.

Merck Sharp & Dohme LLC

Blood and Lymph Conditions

Immune System Diseases

Rare Diseases

Lymphoma

Lymphoma, Mantle-Cell

Neoplasms by Histologic Type

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Lymphoma, Non-Hodgkin

Lymphosarcoma

Mantle Cell Lymphoma

Amino Acids

Antibodies

Antibodies, Monoclonal

Obinutuzumab

Immunoglobulins

Pirtobrutinib

Muromonab-CD3

Antineoplastic Agents, Immunological

Immunoglobulins, Intravenous

Antibodies, Bispecific

Immunologic Factors

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

Participants receive obinutuzumab IV on days 1 and 2 of cycle 1 for a total of 2 doses. Participants receive glofitamab IV on days 8 and 15 of cycle 1 and day 1 of remaining cycles. Cycles repeat every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Participants receive pirtobrutinib PO once a day (QD) on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Participants also undergo FDG-PET/CT at screening, after every 4 cycles through cycle 13 and then after every 6 cycles. Participants will undergo a bone marrow biopsy and aspiration at cycle 13 and blood sample collection throughout study and a tissue biopsy at relapse or progression.

Glofitamab

Biospecimen Collection

ClonoSEQ is an FDA-cleared, Clinical Laboratory Improvement Amendments of 1988 (CLIA)-validated measure used to determine minimal residual disease (MRD). This helps uncover how much, if any, cancer remains in your body during and after treatment.

ClonoSeq Assay

Undergo bone marrow biopsy and aspiration.

Bone Marrow Biopsy

Morgan Tate

C. Babis Andreadis, MD

This phase II trial tests the safety and effectiveness of glofitamab given in combination with pirtobrutinib in treating patients with mantle cell lymphoma that has come back after a period of improvement (relapsed) or that has not responded to previous treatment (refractory). Glofitamab and obinutuzumab are monoclonal antibodies that may interfere with the ability of cancer cells to grow and spread. Obinutuzumab may also reduce the risk of immune-related conditions from treatment. Pirtobrutinib is in a class of medications called kinase inhibitors. It works by blocking the action of the protein that signals cancer cells to multiply. Giving glofitamab in combination with pirtobrutinib may be safe, tolerable and/or effective in treating patients with relapsed or refractory mantle cell lymphoma.

PRIMARY OBJECTIVES:

I. To characterize the safety and tolerability of the combination of glofitamab and pirtobrutinib in the first six patients enrolled.

II. To evaluate the preliminary efficacy of glofitamab and pirtobrutinib in patients with relapsed or refractory mantle cell lymphoma (MCL) as measured by complete response rate.

SECONDARY OBJECTIVES:

I. To evaluate the preliminary efficacy of glofitamab and pirtobrutinib in patients with relapsed or refractory MCL as measured by progression-free survival and overall survival.

II. To characterize the magnitude and duration of anti-tumor activity by objective response rate and duration of response.

III. To characterize the safety and tolerability of the combination of glofitamab and pirtobrutinib.

IV. To evaluate the preliminary efficacy of glofitamab and pirtobrutinib in patients with relapsed or refractory MCL as measured by complete response without measurable disease (CRMRD-) rate.

V. To evaluate the time-to-complete response without measurable residual disease (CRMRD-).

VI. To evaluate the treatment-free interval among patients who discontinue treatment following CRMRD- status.

EXPLORATORY OBJECTIVES:

I. To explore associations between baseline tumor characteristics including genetic (e.g. mutations in BTK) and immune profiles (e.g. expression of co-inhibitory receptors and T cell phenotypes) and outcomes in patients administered the combination of glofitamab and pirtobrutinib.

II. To explore the effects of the combination of glofitamab and pirtobrutinib on pharmacodynamic markers relating to drug mechanism (e.g. emergence of clones with mutations conferring resistance to the study combination).

III. To estimate the quality of life of participants during therapy with glofitamab and pirtobrutinib.

IV. To explore time-to-CRMRD- during therapy with glofitamab and pirtobrutinib.

OUTLINE:

Patients receive obinutuzumab intravenously (IV) on days 1 and 2 of cycle 1 for a total of 2 doses. Patients receive glofitamab IV on days 8 and 15 of cycle 1 and day 1 of remaining cycles. Cycles repeat every 21 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Patients receive pirtobrutinib orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Patients also undergo fludeoxyglucose F-18 (FDG)-positron emission tomography (PET)/computed tomography (CT) at screening, after every 4 cycles through cycle 13 and then after every 6 cycles. Patients additionally undergo echocardiography (ECHO) or multigated acquisition scan (MUGA) at screening, a bone marrow biopsy and aspiration at cycle 13 and blood sample collection at screening and throughout study. Additionally, patients may undergo a tissue biopsy at relapse or progression.

After completion of study treatment, patients are followed up every 3 months for up to 2 years from the start of treatment.

Glofitamab With Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma

A Multicenter Phase 2 Study of Glofitamab With Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma

The severity of the toxicities will be graded according to the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version (v)5.0. AEs and clinically significant laboratory abnormalities meeting grade 3 4 or 5 will be summarized by maximum intensity and relationship to study drug.

CR will be defined as the proportion of treated participants who experience a CR per Lugano criteria among evaluable participants. The Lugano classification recommends the Deauville five-point scale for reporting response by FDG PET-CT: (1) no uptake or no residual uptake (when used interim) (2) slight uptake, but below blood pool (mediastinum) (3) uptake above mediastinal, but below or equal to uptake in the liver (4) uptake slightly to moderately higher than liver (5) markedly increased uptake or any new lesion (on response evaluation).

PFS will be defined as the time that elapses between initiation of trial therapy and the earlier of the day of first documented disease progression or death from any cause. Progression is defined by Lugano criteria of (1) new or increased adenopathy; an individual node must be abnormal with: (a) longest transverse diameter (LDi) \>1.5 cm AND (2) splenic volume increase (3) new or larger non-measured lesions (4) recurrent previously resolved lesions (5) new extranodal lesion \>1 cm in any axis (new lesions \<1 cm in any axis are included if these are "unequivocally attributable" to lymphoma) (6) a new node \>1.5 cm in any axis . PFS will be summarized using Kaplan-Meier method.

OS will be defined as the time that elapses between the initiation of trial therapy and the date of death from any cause for all evaluable participants. OS will be summarized using Kaplan-Meier method.

OR will be defined as the proportion of treated patients who experience an objective response (CR or partial response (PR) per Lugano criteria) among evaluable patients.

DOR will be defined as the time that elapses between the day of first documented response to trial therapy (CR or PR, whichever is first recorded) and subsequent disease progression.

CRMRD will be defined as the achievement of =\< 1 x 10-6 malignant cells in peripheral blood, as assessed by ClonoSEQ assay in a participant who meets all other criteria for CR.

Time to CRMRD will calculate the time that elapses between the initiation of trial therapy and the day of first documented CRMRD and summarized using Kaplan-Meier method.

Treatment-free interval will be defined as the time that elapses from CRMRD status to the time of recurrence and summarized using Kaplan-Meier method.

Eli Lilly and Company

Genentech, Inc.

Adaptive Biotechnologies

C. Babis Andreadis

Principal Investigator

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

Skin and Connective Tissue Diseases

Neurofibromatoses

Neurofibromatosis 1

Neurofibroma

Nerve Sheath Neoplasms

Neoplasms, Nerve Tissue

Syndrome

Neoplastic Syndromes, Hereditary

Neurocutaneous Syndromes

Heredodegenerative Disorders, Nervous System

Neurodegenerative Diseases

Genetic Diseases, Inborn

Peripheral Nervous System Diseases

Neuromuscular Diseases

Nervous System Neoplasms

Peripheral Nervous System Neoplasms

Neurofibromatosis

Neurofibromatosis Type 1

Men and women between 20 and 50 years of age diagnosed with NF1 and their biological parents are eligible for this study.

Douglas R Stewart, M.D.

This study will explore the growth of dermal neurofibromas (skin tumors) in patients with neurofibromatosis type 1 (NF1). Investigators will try to learn: 1) how fast (or slow) these benign tumors grow in NF1, 2) how often new tumors appear and 3) what genes are involved in the growth of the tumors.

Men and women between 20 and 50 years of age diagnosed with NF1 and their biological parents are eligible for this study.

Patients with NF1 are evaluated at the NIH Clinical Center with the following tests and procedures:

* Medical examination and drawing of family tree.
* Photos of the back, abdomen and thigh in order to count the number of skin tumors.
* Photos of the skin taken with a special camera (Primos camera) that takes very detailed pictures of a small area of skin.
* Photos of the skin taken with a dermatoscope, which takes very detailed pictures of a small area of skin under high magnification.
* Biopsy of at least one skin tumor and biopsy of a small piece of normal skin.
* Blood sample collection for genetic testing of the gene NF1 and to establish a cell line.
* Other medical tests (e.g., x-rays or MRI) if needed.

Patients and their families will also have a genetic counseling session and an opportunity to ask questions about neurofibromatosis type 1.

Patients return to the NIH after 3, 6, 12, 18 and 24 months for follow-up photographs and possibly blood samples.

Biological parents of patients provide a blood sample for genetic testing.

This protocol results from a funded 2005 Bench-to-Bedside Award and explores the genetic basis of disease severity in neurofibromatosis type 1 (NF1) and the evaluation of three methods to measure disease progression of dermal neurofibromas. NF1 is a common multisystem genetic disorder associated with the development of benign and malignant tumors, primarily of the nervous system. NF1 is 100% penetrant and features variable expressivity and limited phenotype/genotype correlation. No standard treatment other than surgery exists for most NF1-associated tumors. Many aspects of the natural history of NF1-associated tumors are not fully characterized and require investigation to assess the effects of potential new treatments, in future clinical trials. The development of medical treatments for NF1-associated tumors is an important goal given their morbidity and the lack of non-surgical treatment options. The ability to predict the ultimate severity of disease would have a significant impact on the management and treatment of individuals with NF1.

Sorafenib (BAY 43-9006) is a novel, orally bioavailable agent that targets downstream effectors in the Ras signaling pathway (a key dysregulated pathway in NF1). It has thus a strong scientific rationale for evaluation in NF1 related tumors. Dermal neurofibromas occur in nearly every individual with NF1, and are a significant cosmetic problem and a major cause of morbidity. This protocol will 1) quantify the growth of dermal neurofibromas in NF1 with 3 different imaging modalities 2) use an innovative gene expression method to identify genetic modifiers of dermal neurofibroma burden, and 3) evaluate dermal neurofibromas and normal skin for the presence of targets of sorafenib. Successful validation of reliable quantitative imaging methods of dermal neurofibroma growth is a logical prerequisite to subsequent clinical trials with medical treatments, which will evaluate the effect of new agents on the growth rate of dermal neurofibromas. Identification of genetic modifiers may permit prediction of ultimate tumor burden. Evaluation of targets of new agents in dermal neurofibromas will allow for more rationale drug development for NF1. Given the paucity of protocols for adults with NF1 and dermal neurofibromas, this study will likely generate great interest among affected individuals and have rapid accrual.

Natural History and Biology of Skin Neurofibromas in Neurofibromatosis Type 1

Natural History and Biology of Dermal Neurofibromas in Neurofibromatosis Type 1

.De-identified clinical data will be shared with collaborators under appropriate agreements.

Evaluate the natural history of dermal neurofibromas in NF1 by monitoring the growth rate and development of new dermal neurofibromas using three different complementary imaging modalities over time in individuals with NF1. The study will be adequately powered so that a minimally meaningful statistical definition of progression can be developed for use in subsequent treatment protocols.

Screen for genetic modifiers of dermal neurofibroma burden and growth using a novel approach employing the genetics of gene expression and family-based tests of association. Characterization of gene expression profiles in lymphoblastoid cell lines (LCLs) and dermal neurofibromas predictive of tumor behavior (e.g. growth rate) will also be explored.

Validate sorafenib as a rational agent for clinical development in individuals with NF1-related dermal neurofibromas. Quantify thelevel of expression of the targets of sorafenib by gene expression microarray of both normal skin and of the dermal neurofibromasthemselves. A tissue microarray from formalin-fixed neurofibromas may also be developed to investigate the expression of other therapeutic targets.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Trafficking of Indium-III-Labeled Cultured Immune Cells in Patients Undergoing Immunotherapy for Advanced Cancer	NCT00026897	Neoplasm	Gamma-camera im... Low-risk biopsy	-	National Institutes of Health Clinical Center (CC)
KEYMAKER-U01 Umbrella Master Study: Studies of Investigational Agents With Either Pembrolizumab (MK-3475) Alone or With Pembrolizumab PLUS Chemotherapy in Participants With Advanced Non-small Cell Lung Cancer (NSCLC) (MK-3475-U01/KEYMAKER-U01)	NCT04165798	Carcinoma, Non-...	Tumor Imaging Tumor Tissue Co... Blood Sample Co...	18 Years -	Merck Sharp & Dohme LLC
Glofitamab With Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma	NCT06252675	Mantle Cell Lym...	Obinutuzumab Glofitamab Pirtobrutinib Tumor Imaging Biospecimen Col... ClonoSeq Assay Bone Marrow Bio...	18 Years -	University of California, San Francisco
Natural History and Biology of Skin Neurofibromas in Neurofibromatosis Type 1	NCT00314119	Neurofibromatos... Neurofibroma		20 Years - 99 Years	National Institutes of Health Clinical Center (CC)
Trafficking of Indium-III-Labeled Cultured Immune Cells in Patients Undergoing Immunotherapy for Advanced Cancer	NCT00026897	Neoplasm	Gamma-camera im... Low-risk biopsy	-	National Institutes of Health Clinical Center (CC)
Glofitamab With Pirtobrutinib for Relapsed or Refractory Mantle Cell Lymphoma	NCT06252675	Mantle Cell Lym...	Obinutuzumab Glofitamab Pirtobrutinib Tumor Imaging Biospecimen Col... ClonoSeq Assay Bone Marrow Bio...	18 Years -	University of California, San Francisco

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