A Phase 1/2 First-in-Human Open-Label Dose Escalation Study of Talquetamab a Humanized GPRC5D x CD3 Bispecific Antibody in Subjects with Relapsed or Refractory Multiple Myeloma
This is a Phase 1/2 first-in-human (FIH) study of the humanized immunoglobulin G4 proline, alanine, alanine (IgG4 PAA) bispecific antibody, talquetamab, which was developed to evaluate the therapeutic potential of targeting GPRC5D for T cell redirection. The antibody binds to the CD3 receptor complex on T cells and to GPRC5D on plasma cells. It is hypothesized that by inducing enhanced T cell-mediatedcytotoxicity through recruitment of CD3-expressing T cells to the GPRC5D-expressing cells, treatment with talquetamab will be an effective therapy for subjects with multiple myeloma.Part 1 and Part 2 of the study are considered Phase 1; Part 3 of the study is considered Phase 2. Part 1 and Part 2 will enroll subjects with relapsed or refractory multiple myeloma. Part 3 will enroll subjects with relapsed or refractory multiple myeloma in the following 2 cohorts that differ by prior therapy:? - Cohort A will enroll subjects with multiple myeloma who have previously received =3 prior lines of therapy that included at least one proteasome inhibitor (PI), one immunomodulatory imide drug (IMiD), and an anti-CD38 monoclonal antibody, and have not been exposed to T cell redirection therapies such as CAR-T or bispecific antibodies.? - Cohort B will enroll subjects with multiple myeloma who have previously received =3 prior lines of therapy that included at least one PI, one IMiD, and an anti-CD38 monoclonal antibody, and have been exposed to T cell redirection therapies such as CAR-T or bispecific antibodies.
A Phase 1/2 First-in-Human Study of DCC-3116 as Monotherapy and in Combination with RAS/MAPK Pathway Inhibitors in Patients with Advanced or Metastatic Solid Tumors with RAS/MAPK Pathway Mutations
Study DCC-3116-01-001 is a FIH study of DCC-3116 to evaluate safety and preliminary activity of DCC-3116 as monotherapy, and in combination with the mitogen activated protein kinase kinase (MAPK/ERK kinase=MEK) inhibitor trametinib, the MEK inhibitor binimetinib, and in combination with a KRAS G12C inhibitor, sotorasib. The objective of the study is to identify the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of DCC-3116 as monotherapy and in combination with trametinib, or binimetinib or sotorasib in the Dose Escalation Phase (Part 1).The purpose of Expansion Cohorts 1 through 3 in the Dose Expansion Phase (Part 2) is to demonstrate the antitumor activity of DCC-3116 combination with trametinib in RAS/MAPK pathway mutant tumors where autophagy has been implicated as a mechanism of resistance to MAPK pathway inhibitors such as the MEK inhibitor, trametinib. The RP2D of the combination with trametinib (RP2D-CT) will be used in 3 expansion cohorts (Figure 2) to further evaluate safety and efficacy of the combination. As described above, DCC-3116 inhibits autophagy induced by the treatment with trametinib, and the combination of DCC-3116 with trametinib showed antitumor activity in various xenograft models with RAS/MAPK pathway mutant tumors including pancreatic ductal adenocarcinoma (PDAC), non-small cell lung cancer (NSCLC), colorectal cancer (CRC), and melanoma.The purpose of Expansion Cohort 4 in the Dose Expansion Phase (Part 2) is to demonstrate the antitumor activity of DCC-3116 in combination with binimetinib in NRAS mutant melanoma. The RP2D of the combination with binimetinib (RP2D-CB) will be used in Expansion Cohort 4 (Figure 2) to further evaluate safety and efficacy of the combination. Like trametinib, binimetinib inhibits MEK and preclinical studies in xenograft models have demonstrated improved anticancer efficacy in combination with DCC-3116. While more clinical data exist for trametinib as monotherapy in other solid cancers, in NRAS mutant melanoma binimetinib monotherapy has been studied more (Dummer et al, 2017). Therefore, binimetinib is planned for use in Expansion Cohort 4 (NRAS mutant melanoma), while trametinib is planned for use in Expansion Cohorts 1 to 3. However, if preliminary PK, PD, safety, and efficacy analyses suggest a more favorable profile for the combination of DCC-3116 with trametinib or binimetinib, Expansion Cohorts 1 to 4 may use the same MEK inhibitor.The purpose of Expansion Cohort 5 (Figure 2) in the Dose Expansion Phase (Part 2) is to demonstrate the antitumor activity of DCC-3116 in combination with sotorasib, a small molecule covalent inhibitor of KRAS G12C. The RP2D of the combination with sotorasib (RP2D-CS) will be used in Expansion Cohort 5 to further evaluate safety and efficacy of the combination. Sotorasib is a small molecule covalent inhibitor of KRAS G12C, with demonstrated efficacy in treatment of patients with KRAS G12C-mutated locally advanced or metastatic NSCLC. Sotorasib blocks KRAS signaling, inhibits cell growth, and promotes apoptosis in KRAS G12C tumor cell lines, but also activates autophagy which promotes cancer cell survival as a mechanism of drug resistance. DCC-3116 blocks this autophagy and thus synergizes with KRAS G12C inhibitor sotorasib, causing tumor regression in KRAS mutant NSCLC xenograft models.
A Phase 1/2 First-Time-in-Human open-label multicenter dose escalation and expansion study of the oral DNA Helicase Werner Inhibitor (WRNi) GSK4418959 alone or in combination with other anti-cancer agents in adult participants with Mismatch Repair-deficient (dMMR) or Microsatellite Instability-High (MSI-H) solid tumors (SYLVER)
This study will test how well the oral WRN inhibitor GSK4418959 works and whether it has few side effects, both by itself and with dostarlimab, in patients with advanced cancers that have specific genetic markers called dMMR/MSI-H, including colorectal and endometrial cancer. First, patients will go through a pre-screening process to check if their tumors have these markers and see if they qualify. Those who qualify will join one of three parts of the study: Part 1 will test different doses of GSK4418959 alone in patients with advanced tumors; Part 2 will use the best dose from Part 1 to test the drug in patients with advanced colorectal or endometrial cancer; and Part 3 will test different doses of GSK4418959 combined with dostarlimab in patients with advanced tumors.
A Phase 1/2 Multiple Expansion Cohort Trial of MRTX1719 in Patients with Advanced Solid Tumors with Homozygous MTAP Deletion
This study is testing the effectiveness of a new drug, MRTX1719, in patients with advanced solid tumors that have a specific genetic change called MTAP deletion. The study follows guidelines from the U.S. Food and Drug Administration (FDA). The study starts with Phase 1, which will test different doses of MRTX1719 to find the most effective one with less sideeffects. In Phase 2, MRTX1719 will be tested in different groups of patients based on their type of cancer and other characteristics to see how well the drug works and how safe it is. There are plans to make changes during the study to prepare for future tests, depending on the results. The study includes careful monitoring, genetic testing to confirm eligibility, andregular checks on how the drug affects the patients.
A Phase 1/2 Multiple Expansion Cohort Trial of MRTX849 in Patients with Advanced Solid Tumors with KRAS G12C Mutation
Study 849-001 is a multi-center, Phase 1/2, multiple expansion cohort trial evaluating the safety, PK, metabolites, PD and clinical activity/efficacy of MRTX849 in patients with advanced solid tumor malignancies with KRAS G12C mutation. This protocol is designed as recommended in US FDA draft guidance for conduct of first-in-human multiple expansion cohort trials (FDA-2018). Oversight of this clinical trial is provided by the Sponsor, Investigators, local IRBs, a specifically commissioned Central IRB and an IDMC. Plans for communication of emerging study results are outlined in Section 9.9.3. Plans for communication of study decisions and protocol changes are outlined in Section 13.2.
A Phase 1/2 Open-Label Study to Evaluate the Safety Tolerability Pharmacokinetics and Efficacy of TNG260 as Single Agent and in Combination with an anti-PD-1 Antibody in Patients with STK11-Mutated Advanced Solid Tumors
This is a first-in-human Phase 1/2, open-label, multicenter, dose-escalation and -expansionstudy designed to determine the MTD of TNG260 as single agent and in combination withpembrolizumab, to determine the RP2D(s) of the combination, and to evaluate the safety andtolerability, PK, and antineoplastic activity of escalating oral doses of TNG260 whenadministered alone and with a standard dose of pembrolizumab in participants with locallyadvanced or metastatic STK11-mutated solid tumors who have progressed on at least 1 lineof standard therapy or are ineligible for standard therapies.In Phase 1 (dose escalation), at least 3 DLT-evaluable participants will be enrolled insequentially escalating dose cohorts to determine the MTD of single agent TNG260, theMTD of the combination of TNG260 and pembrolizumab, and the RP2D(s) of TNG260 incombination with a standard dose of pembrolizumab. The dose escalation of TNG260 will beguided by two BLRMs based on any DLTs observed in the first cycle (ie, the first 21 days) ofthe single agent therapy and the second cycle for the combination therapy.Participants in Phase 2 (dose expansion) will be dosed at the RP2D(s) determined fromPhase 1 based on demonstrated tolerability, together with available PK data and results oftarget engagement studied during Phase 1 (or other measures including PD and efficacy), asapplicable. Three Phase 2 combination expansion arms (TNG260 in combination withpembrolizumab) will enroll up to approximately 30 participants each.
A Phase 1/2 Study of LY3537982 in Patients with KRAS G12C-Mutant Advanced Solid Tumors
Study LOXO-RAS-20001 is a first-in-human, multicenter, open-label Phase 1/2 study to evaluate the safety, tolerability, and preliminary efficacy of oral LY3537982 as monotherapy and as part of combination therapy in patients with KRAS G12C-mutant advanced solid tumor types, including but not limited to NSCLC and CRC.This study includes 2 parts, Phase 1a dose escalation (Part A) followed by a Phase 1b dose expansion (Part B-E). The Phase 1a dose escalation LY3537982 monotherapy cohort will enroll any eligible patient with KRAS G12C-mutant advanced solid tumor. Once the LY3537982 monotherapy RP2D (RP2DM) is established, Phase 1b dose expansion will begin and include 10 cohorts (NSCLC, Cohorts B1–B6; CRC, Cohorts C1–C2; other solid tumors [except NSCLC and CRC], Cohort D1; KRAS G12C-mutant advanced NSCLC who have previously been treated with a KRAS G12C inhibitor, Cohort E1) to further evaluate safety and clinical activity.KRAS G12C mutations will be identified through standard of care testing as routinely performed at each participating site utilizing material collected prior to patient consent to this protocol. Molecular assays utilized for enrollment are required to be performed in Clinical Laboratory Improvement Amendments (CLIA), International Organization for Standardization/International Electrotechnical Commission (ISO/IEC), College of American Pathologists (CAP), or other in a similarly certified laboratory.
A PHASE 1/2 STUDY OF REGN5678 (ANTI-PSMAXCD28) WITH OR WITHOUT CEMIPLIMAB (ANTI-PD-1) IN PATIENTS WITH METASTATIC CASTRATION-RESISTANT PROSTATE CANCER AND OTHER TUMORS ASSOCIATED WITH PSMA EXPRESSION
This is an open-label, phase 1/2, first-in-human (FIH) study evaluating safety, tolerability, PK, and anti-tumor activity of REGN5678 (anti- PSMAxCD28) alone and in combination with cemiplimab (anti-PD-1) in treatment-experienced metastatic castration-resistant prostate cancer (mCRPC).There are two parts of the study:? Dose escalation: During dose escalation, patients will receive a 3- week monotherapy lead-in of REGN5678 at the assigned dose level (DL) administered intravenously (IV) weekly (QW) followed by combination therapy of REGN5678 at the assigned DL IV QW and cemiplimab 350 mg IV every 3 weeks (Q3W).? Dose Expansion: During dose expansion, patients will receive combination therapy of REGN5678 at the assigned DL (eg, maximum tolerated dose [MTD]/recommended phase 2 dose [RP2D]) IV QW and cemiplimab 350 mg IV Q3W without a 3- week monotherapy lead-in of REGN5678.Dose expansion cohort(s) will be enrolled after identification of the REGN5678 MTD in combination with cemiplimab and/or RP2D. Prior to enrollment of an expansion cohort, 3 to 6 additional patients will be enrolled at that DL without a 3-week monotherapy lead-in of REGN5678 to further evaluate safety and biologic activity (dose escalation cohorts designated with an asterisk [*cohorts]).Safety evaluations will be conducted at each study drug dosing visit. Radiographic response assessment will be performed every 6 weeks from cycle 1 (C1D42/C2D1) up to cycle 4 (including patients who receive the initial 3-week monotherapy lead-in of REGN5678) and every 12 weeks thereafter.Investigators should continue treating patients with study drug until confirmed disease progression, elective discontinuation for response, per modified PCWG3, intolerable adverse events (AEs), withdrawal of consent, or other study withdrawal criterion is met. Patients who do not withdraw consent will then be expected to continue off-treatment follow-up procedures.
A Phase 1/2 Study of the Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor NVL-655 in Patients with Advanced NSCLC and Other Solid Tumors (ALKOVE-1)
A Phase 1/2 Study of the Selective Anaplastic Lymphoma Kinase (ALK) Inhibitor NVL-655 in Patients with Advanced NSCLC and Other Solid Tumors (ALKOVE-1)
A Phase 1/2 Study to Evaluate the Safety and Efficacy of AZD0486 in Adolescent and Adult Participants with Relapsed or Refractory B-Cell Acute Lymphoblastic Leukaemia
This study is designed to test how effective a new drug called AZD0486 (BITE for CD19) is for patients relapsed/refractory B-cell acute lymphoblastic leukemia (R/R B-ALL) who have already tried at least 1-2 other treatments. This study has three parts: Part A will test increasing doses of AZD0486 to find a dose with few side effects; Part B will test up to two doses from Part A to decide the best dose to use in the next phase; and Part C will use the best dose from Part B to see how well it works in more patients. AZD0486 will be given as an IV infusion on certain days of each 28-day cycle, with close monitoring for side effects. Side effects and effectiveness will be checked regularly, and the study will continue untilenough data is collected to understand how well AZD0486 works and how safe it is.