A Phase 1/1b First-In-Human Multi-Part Open-Label Study to Investigate the Safety Tolerability Pharmacokinetics Biological and Clinical Activity of DF6215 in Patients with Advanced (Unresectable Recurrent or Metastatic) Solid Tumors
This is a study is testing a new drug called DF6215 on patients with tough-to-treat (unresectable, recurrent or metastatic) solid tumors. The goal is to see if the treatment has few side effects and if it is effective in treating the tumors. The study is being done in two parts. First, the study team is testing different doses to find out how much patients can tolerate of DF6215 without getting too sick or without dealing with side effects. Then, the study team will give the best dose from the first part to more patients to see if it helps them with their tumors. The drug will be given through a vein every other week for a month. The study team will keep a close eye on how every patient is doing to make sure the drug is safe and effective.
A Phase 1/1b Open-label Multicenter Study to Investigate the Safety Tolerability Pharmacokinetics and Antitumor Activity of KIN-2787 in Participants with BRAF and/or NRAS Mutation-positive Solid Tumors
This is a 2-part, open-label, multicenter, dose escalation and dose expansion study in participants with rapidly accelerated fibrosarcoma, homolog B (BRAF) mutation-positive and/or neuroblastoma RAS (NRAS) mutation-positive tumors designed to evaluate the safety, tolerability, and pharmacokinetics (PK) of KIN-2787, a pan-rapidly accelerated fibrosarcoma (RAF) small molecule kinase inhibitor; to determine a recommended Phase 2 dose (RP2D) of KIN-2787 for further clinical development; and to assess the objective response to KIN-2787 therapy alone and in combination with binimetinib, a mitogen-activated protein kinase (MEK) inhibitor.
A Phase 1/1b Study of ASP2138 in Participants With Metastatic or Locally Advanced Unresectable Gastric or Gastroesophageal Junction (GEJ) Adenocarcinoma or Metastatic Pancreatic Adenocarcinoma Whose Tumors Have Claudin (CLDN) 18.2 Expression
Claudin 18.2 protein, or CLDN18.2 is a protein found on cells in the digestive system. It is also found on some tumors. Researchers are looking at ways to attack CLDN18.2 to help control tumors. ASP2138 is thought to bind to 2 targets at the same time: CLDN18.2 and a protein called CD3 found on immune cells, called T-cells. ASP2138 works by binding to both the tumor cell and CD3 which "tells" the immune system to attack the tumor.ASP2138 is a potential new treatment for people with stomach cancer, gastroesophageal junction cancer, (cancer where the tube that carries food (esophagus) joins the stomach) or pancreatic cancer. Before ASP2138 is available as a treatment, the researchers need to understand how it is processed by and acts upon the body. This information will help to find a suitable dose and to check for potential medical problems from the treatment.Adults 18 years or older with stomach cancer, gastroesophageal junction cancer, or pancreatic cancer can take part. Their cancer is locally advanced unresectable or metastatic. Locally advanced means the cancer has spread to nearby tissue. Unresectable means the cancer cannot be removed by surgery. Metastatic means the cancer has spread to other parts of the body.The main aims of the study are to check the safety of ASP2138, how well it is tolerated, and to find a suitable dose of ASP2138 to be used later in this study.This is an open-label study. This means that people in this study and clinic staff will know that people will receive ASP2138.The study will have 2 phases. In phase 1, different small groups of people will receive lower to higher doses of ASP2138. Any medical problems will be recorded at each dose. This is done to find suitable doses of ASP2138 to use later in the study. The first group will receive the lowest dose of ASP2138. A medical expert panel will check the results from this group and decide if the next group can receive a higher dose of ASP2138. The panel will do this for each group until all groups have received ASP2138, or until suitable doses have been selected for later in the study. Doctors will also check how each type of cancer is responding to ASP2138.In phase 1b, other different small groups will receive suitable doses of ASP2138 found from phase 1. This phase will check how each type of cancer responds to ASP2138. The response to ASP2138 is measured using scans and blood tests. Doctors will continue to check all medical problems throughout the study.ASP2138 will be given through a vein in the arm. This is called an infusion. People will receive weekly infusions of ASP2138 in a 14-day (2-week) treatment cycle. People will continue to receive treatment until: their cancer gets worse; they have medical problems they can't tolerate; they ask to stop treatment; the doctors decide that continuing treatment is no longer in that person's best interest; the study is ended by the sponsor. Doctors will check if people had any medical problems from ASP2138. Other checks will include medical examinations, checking the nervous system, blood and urine tests and vital signs. Nervous system checks include checking peoples state of mind, reflexes, balance, movement and muscle strength. Vital signs include medical examinations, body temperature, breathing rate, and blood oxygen levels. Electrocardiograms (ECG) will be done to check the heart rhythm during the study. People will receive ASP2138 in a hospital. They will have blood tests and doctors will check for medical problems. People will also visit the clinic on certain days during their treatment, with extra visits during the first 3 cycles of treatment.People will visit the clinic after treatment has finished. The doctors will check for more medical problems. Other checks will include medical examinations, blood and urine tests, and vital signs. People will also have an ECG.After this, people will visit the clinic for a check-up several times. The number of visits and checks done at each visit will depend on the health of each person and whether they completed their treatment or not.
A phase 1/1b/2 study evaluating the safety tolerability pharmacokinetics pharmacodynamics and efficacy of AMG 193 alone and in combination with docetaxel in subjects with advanced MTAP-null solid tumors
The primary objective of Parts 1 and 2 of this study is to evaluate the safety, tolerability, and to determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of AMG 193 alone and in combination with docetaxel in adult participants with metastatic or locally advanced methylthioadenosine phosphorylase (MTAP)-null solid tumors.The primary objective of Part 3 of this study is to evaluate the objective response rate (ORR) of AMG 193 in adult participants with metastatic or locally advanced MTAP-null non-small cell lung cancer (NSCLC), after prior treatment with chemotherapy and/or a programmed death-1/ligand 1 (PD-1/L1) inhibitor.
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 Multi-Center Open-Label Study to Evaluate the Safety Tolerability and Preliminary Anti-tumor Activity of TNG908 in Patients with MTAP-deleted Advanced or Metastatic Solid Tumors
TNG908 is a potent and selective oral small moleculeinhibitor of PRMT5 that binds cooperatively with MTA to inhibit PRMT5 function. Elevatedlevels of MTA are found in tumor cells that have lost the MTAP gene, conveying exquisitespecificity of TNG908 to tumor cells that have lost MTAP over normal tumor cells withintact MTAP gene expression. In vitro data of TNG908 demonstrate strong selectivity forMTAP-deleted cells, and selectivity and potency are demonstrated in MTAP-isogenic celllines representing multiple cancer lineages. It also induces dose-dependent anti-tumoractivity in LN18 MTAP-deleted xenografts and dose-dependent PRMT5 PD modulationconsistent with on-target anti-tumor activity in MTAP-deleted cells. This Phase 1/2 study willestablish an MTD and/or biologically effective dose, support an RP2D, and evaluate theinitial anti-tumor activity and tolerability profile of TNG908 when administered as amonotherapy.
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 Rolling-Arm Umbrella Platform Design of Investigational Agents With or Without Pembrolizumab or Pembrolizumab Alone in Participants with Melanoma (KEYMAKER-U02): Substudy 02C
Substudy 02C is part of a larger research study that is testing experimental treatments for melanoma, a type of skin cancer. The larger study is the umbrella study.The goal of substudy 02C is to evaluate the safety and efficacy of investigational treatment arms in participants with Stage III melanoma who are candidates for neoadjuvant therapy to identify the investigational agent(s) that, when used in combination, are superior to the current treatment options/historical control available.
A Phase 1/2 Open-Label Rolling-Arm Umbrella Platform Design of Investigational Agents With or Without Pembrolizumab or Pembrolizumab Alone in Participants With Melanoma (KEYMAKER-U02): Substudy 02D
The Master Protocol is a Phase 1/2, rolling arm, multicenter, open-label, adaptive design study that will evaluate within this substudy protocol the efficacy of investigational agents with or without pembrolizumab for the treatment of PD-1 naïve or PD-1 exposed participants with MBM. Preliminary efficacy from this substudy protocol will be evaluated by using ORR per RECIST 1.1 as determined by BICR.In this substudy protocol, an investigational treatment arm refers to a unique investigational agent or a combination of investigational agents with or without pembrolizumab. Investigational agents will only be added to this substudy protocol after an initial evaluation of safety and tolerability when administered alone and in combination with pembrolizumab has been completed and a RP2D has been identified. Specific procedures to be performed during the study, including prescribed times and associated visit windows, are outlined in the SoA in Appendix 6, Section 10.6.2.1.Approximately 50 participants will be enrolled in each investigational treatment arm of this substudy protocol. Investigational treatment arm(s) within the PD-1 naïve cohort (Cohort 1) may be expanded to 100 participants based on the totality of evidence.