Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

All Conditions

Digestive System Diseases

Gland and Hormone Related Diseases

Skin and Connective Tissue Diseases

Nervous System Diseases

Diseases and Abnormalities at or Before Birth

Rare Diseases

Lung Neoplasms

Pancreatic Neoplasms

Melanoma

Glioblastoma

Brain Neoplasms

Central Nervous System Neoplasms

Neurofibromatoses

Neurofibromatosis 1

Pancreatic Cancer

Neurofibromatosis

Neurofibromatosis Type 1

Herbal and Botanical

All Drugs and Chemicals

Cola

A classic "3+3" design will be used to explore the maximum tolerated dose (MTD) and to determine the recommended phase II dose (RP2D). Three to four patients will be enrolled to ensure at least 3 evaluable patients for DLT (Dose Limiting Toxicity). ABM-168 monotherapy will be conducted in seven provisional dose levels starting at 0.5mg oral administration per day and up to and including 12mg oral administration. Each treatment cycle is 28-days. DLT will be evaluated in the first 28-day cycle. Patients will receive daily doses of ABM-168 until disease progression; intolerable toxicity; withdrawal consent; or other clinical observation is met.

Expansion will be conducted in the adult patients with advanced solid tumors that carry either RAS, RAF or NF-1 mutations. Cohort EX1 will enroll the patients with preferred indications (i.e., melanoma, colon cancer, lung cancer, and pancreatic carcinoma) who had confirmed RAS, RAF or NF-1 mutations and measurable target lesion(s) at baseline. Patients with measurable brain metastases lesion(s) at baseline are highly preferred. Up to 15 evaluable patients will be enrolled for each into each preferred indication. Other indication(s) that show confirmed response, complete response (CR) or partial response (PR) in at least one subject in the dose escalation study will facilitate the preferred indication(s) for Cohort EX1 enrollment as well.

Expansion will be conducted in the adult patients with advanced solid tumors that carry either RAS, RAF or NF-1 mutations. Cohort EX2 will enroll the patients who had primary CNS tumors with confirmed RAS, RAF or NF-1 mutations at baseline. Up to 30 evaluable patients will be enrolled.

Dosage: 0.5 mg; 2 mg; 6 mg; once daily by oral administration

ABM-168

Katie Zhou

Michael Wong

Katy Tsai, M.D.

Mateusz Opyrchal, M.D.

Suzanne Bailey

Taryn Bollaro

Sanjay Goel, MD

Rabia Khan

Sarina A. Piha-Paul, M.D.

Shiraj Sen, MD, PhD

Ignacio Garrido-Laguna, M.D.

Jamie White

This is a Phase 1, First-in-Human (FIH), open-label, multicenter, dose escalation and dose expansion study to evaluate the safety, tolerability, pharmacokinetics and preliminary anti-tumor activity of ABM-168 in adult patients with RAS or RAF or NF-1 mutated advanced solid tumors as ABM-168 may have a significant effect in inhibiting cell growth.

This is a First-in-Human (FIH), open-label, multicenter, dose escalation and dose expansion, Phase I study of ABM-168, for the treatment of advanced solid tumors in adult patients.

The study consists of two parts:

Part A: Dose escalation. The starting dose of ABM-168 is 0.5 mq po qd, and dose escalation will be guided by a "3+3" design. ABM-168 will be administered once daily on a continuous schedule. Each treatment cycle consists of 28 days.

Part B: Dose Expansion. Expansion will be conducted in the adult patients with advanced solid tumors that carry either RAS, RAF or NF-1 mutations. There are two cohorts for Dose Expansion: Patients will be enrolled into either Dose Expansion Cohort 1 (EX1) or Dose Expansion Cohort 2 (EX2).

* Cohort EX1: Patients enrolled will have preferred indications (i.e., melanoma, colon cancer, lung cancer, and pancreatic carcinoma) who had confirmed RAS, RAF or NF-1 mutations and measurable lesion(s) at the beginning of the study. Patients with measurable brain lesions(s) which have metastasized are highly preferred.
* Cohort EX2: Patients enrolled will have primary CNS (Central Nervous System tumors with confirmed RAS, RAF or NF-1 mutations.

Dose limiting toxicity (DLT) will be evaluated and managed per the pre-defined DLT criteria and rules specified in the protocol. MTD (Maximum Tolerated Dose) and/or RP2D will be determined based on the totality of safety, clinical pharmacokinetics, and efficacy data from all evaluable patients enrolled and in treated in both dose escalation cohorts and dose expansion cohorts. The RP2D (recommended phase II dose) could be the MTD, or alternatively a dose recommended by the SMC (Safety Monitoring Committee) if no MTD is determined in the dose escalation and/or dose expansion.

Study consists of two parts:

* Part A: ABM-168 Dose Escalation and DLT Dose Confirmation
* Part B: Dose Expansion (ABM-168 Monotherapy)

Safety and Effectiveness of ABM-168 in Adults With Advanced Solid Tumors.

A Phase I, First-In-Human, Multicenter, Open Label, Dose Escalation and Dose Expansion Study to Evaluate the Safety and Efficacy of ABM-168 Administered Orally in Adult Patients With Advanced Solid Tumors

Dose limiting toxicities (DLT) which defines the MTD/RP2D

Safety and tolerability of ABM-168 monotherapy as determined by incident rate.

Safety and tolerability of ABM-168 monotherapy as determined by severity. Adverse events will be assessed according to the National Cancer Institute (NCI) Common Toxicity Criteria for Adverse Events (CTCAE) version 5.0. For consistency, Version 5.0 will be used throughout the trial regardless of any subsequent versions of the CTCAE criteria that may become available. If CTCAE grading does not exist for a specific adverse event, the severity should be assessed based on the general guidelines outlined in CTCAE v5.0.

Safety and tolerability of ABM-168 monotherapy as determined by causality of adverse events (AEs).

Safety and tolerability of ABM-168 monotherapy as determined by clinically significant abnormalities in clinical laboratory testing.

Safety and tolerability of ABM-168 monotherapy as determined by body temperature changes from base-line in Fahrenheit.

Safety and tolerability of ABM-168 monotherapy as determined by heart rate changes from base-line in BPM (beats per minute).

Safety and tolerability of ABM-168 monotherapy as determined by pulse rate changes from base-line in BPM (beats per minute).

Safety and tolerability of ABM-168 monotherapy as determined by respiratory rate changes from base-line in breaths per minute.

Safety and tolerability of ABM-168 monotherapy as determined by blood pressure changes from base-line in systolic blood pressure (measured in mmHg).

Safety and tolerability of ABM-168 monotherapy as determined by blood pressure changes from base-line in diastolic blood pressure (measured in mmHg).

Safety and tolerability of ABM-168 monotherapy as determined by ophthalmology assessment.

Safety and tolerability of ABM-168 monotherapy as determined by ECGs (QT interval).

Safety and tolerability of ABM-168 monotherapy as determined by ECOG scores (0-Fully active; - 5-Dead).

Safety and tolerability of ABM-168 monotherapy as determined by Karnofsky performance scores - 70 (able to care for self and live at home) - 100 (able to carry on normal activity).

ABM Therapeutics Corporation

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Antineoplastic Agents

Capecitabine

Aflibercept

Antimetabolites

Angiogenesis Inhibitors

Growth Inhibitors

A standard 3+3 dose escalation format will be used. Capecitabine will start at 850mg/m2 to be given on days 1-14 and off days 15-21. If tolerated, the dose will then be escalated to 1000mg/m2 for the next cohort, given on the same schedule. The dose of aflibercept will be held constant at 6 mg/kg, given intravenously every 3 weeks.

Once the RPTD of the doublet combination has been identified, an additional 50 subjects with metastatic colorectal cancer will be added to a single, Phase 2 arm

Capecitabine given on days 1-14 and off days 15-21. Dose: Phase 1 cohort 1 850mg/m2 Phase 1 cohort 2 1000mg/m2, Phase 2 RPTD.

Aflibercept will be held constant at 6 mg/kg, given intravenously every 3 weeks.

Both agents will be administered on a 21-day cycle.

Capecitabine and aflibercept

John Strickler, MD

The Primary Phase I objectives are to determine the recommended phase II dose for the capecitabine and aflibercept doublet combination; and to describe any dose limiting and non-dose limiting toxicities. The Phase II Primary objective is to determine progression free survival associated with this regimen. The Phase II secondary objectives are to determine response rate associated with this regimen; to determine overall survival associated with this regimen; and to explore any correlation of clinical outcome with baseline and on treatment changes in blood-based angiogenesis biomarkers.

This open-label, non-randomized phase I/II trial is designed to assess the safety, tolerability and RPTD of capecitabine plus aflibercept in adult subjects with metastatic colorectal cancer.

Phase I/II Study of Capecitabine Plus Aflibercept to Treat Metastatic Colorectal Cancer

X-TRAP: Phase I/II Study of Capecitabine Plus Aflibercept in Metastatic Colorectal Cancer

Phase 1 of this study will be the dose escalation component to determine safety and the Recommended Phase II dose (RPTD) for the capecitabine plus aflibercept combination. Cohort 1 will receive 850mg/m2 capecitabine and 6mg/kg aflibercept. If less than 2 of 6 patients experience a dose limiting toxicity in Cohort 1, then the next patients will be enrolled in Cohort 2 at 1000mg/m2 capecitabine and 6mg/kg aflibercept. RPTD is determined by the number of dose limiting toxicities (Primary obj 2 for Phase I).

Number of patients experiencing a dose-limiting toxicity in each cohort.

A dose-limiting toxicity is defined as Grade 4 neutropenia, thrombocytopenia or anemia or grade 3 neutropenia or thrombocytopenia lasting over 7 days Grade 3 thrombocytopenia associated with bleeding Febrile Neutropenia Nausea/Vomiting or Diarrhea ≥ grade 3 and lasting ≥ 4 days despite adequate supportive measures Grade ≥ 3 Bilirubin, ALT or AST \> 7 days Other non-hematologic toxicity ≥ grade 3 excluding alopecia, anorexia, fatigue, hypertension, isolated lab abnormalities (not clinically significant) and/ rare, idiosyncratic reactions to any of the study drugs. Anorexia, fatigue and hypertension will be considered as DLT only if they reach grade 4 or are considered unmanageable Treatment delay of ≥ 14 days for cycle 2 due to unresolved toxicity Treatment-related death or clinically significant,treatment-related hospitalization

Time in months from the start of study treatment to the date of first progression (PD) according to the RECIST criteria, or death due to any cause. Per RECIST criteria, a PD is indicated when there is at least a 20% increase in the sum of the longest diameters from target lesions relative to the smallest sum recorded since treatment is initiated. Median PFS was estimated using a Kaplan-Meier curve, and is the time at which 50% of patients remain alive without disease progression.

The percentage of patients for whom the best overall response is complete response (CR) or partial response (PR). A CR occurs when all lesions disappear; whereas, a PR is indicated when there is at least a 30% decrease in the sum of the longest diameters (LD) of the target lesion. A PD (progressive disease) occurs when there is at least a 20% increase in the sum of the LD relative to the smallest sum LD recorded since treatment is initiated. Disease is considered stable if there is no response and no PD. All patients were assigned a best response for inclusion in this calculation in accordance with the protocol.

Time in months from the start of study treatment to date of death due to any cause. Median survival was estimated using a Kaplan-Meier curve and is the time point at which 50% of patients remain alive.

Sanofi

John Strickler, M.D.

Associate Professor

Grade 2 and above adverse events for this study were collected using Common Terminology Criteria for Adverse Events (CTCAE) version 4.0.

Capecitabine is given days 1-14 of a 21 day cycle. Cohort 1 will receive 850mg/m2 Capecitabine and Cohort 2 will receive 1000mg/m2. Aflibercept 6 mg/kg is given intravenously every 3 weeks.

Phase 1

Capecitabine at the recommended dose based on Phase 1 (850mg/m2) given on days 1-14. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.

Phase 2

Total

Age, Continuous

Sex: Female, Male

Race (NIH/OMB)

United States

Region of Enrollment

Aflibercept 6 mg/kg given intravenously every 3 weeks. Capecitabine was given at 850mg/m2 for the first cohort and at 1000mg/m2 for the second cohort.

Recommended Phase II Dose (RPTD) for the Capecitabine and Aflibercept Doublet Combination

Capecitabine 850mg/m2 given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.

Phase 1 Cohort 1

Capecitabine 1000 mg/m2 given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.

Phase 1 Cohort 2

Number of Dose-Limiting Toxicities (Phase 1)

Capecitabine at the recommended dose based on Phase 1, given days 1-14 and off days 15-21. Aflibercept 6 mg/kg given intravenously every 3 weeks. Both agents are administered on a 21-day cycle.

Patients enrolled in Phase 2 were included in the analysis

Median Progression Free Survival (PFS)

All evaluable Phase 2 patients. 5 patients were not evaluable for response and were not included in the analysis.

Response Rate

Median Survival

Overall Study

Dermatologic Agents

Antibodies

Immunomodulating Agents

Immunoglobulins

Coal Tar

Subjects with advanced solid tumors already on ICI will receive treatment with MET-4 in addition to SOC ICI. MET-4 is administered orally as an initial daily loading dose (5g) of MET-4 over 2 days followed by a daily maintenance dose (1.5g) of MET-4 and will be continued until unacceptable toxicity, progression of disease

Eligible subjects with advanced solid tumors starting ICI will be randomised in a 3:1 ratio stratifying for prior IO exposure, to receive MET-4 together with any approved PD-1/PD-L1 inhibitor as per SOC or control group. There will be a run-in period for subjects in the MET-4 treatment group. Following the run-in period of ICI therapy, subjects will be administered the same MET-4 dose as subjects in group A.

In group C, eligible subjects with advanced solid tumors whom are already on ICI with first unconfirmed PD on evaluation scans per investigator's assessment, will be randomised in a 1:1 ratio to receive MET-4 in addition to the PD-1/PD-L1 inhibitor as per SOC or control group. These subjects must be clinically stable and are to be continued on ICI at the discretion of the investigator. There will be no run-in period for this cohort. Subjects will be administered the same MET-4 dose as subjects in groups A and B.

In group D, eligible subjects with stage III or resected stage IV melanoma who are to start adjuvant ICI, will be randomized in a 1:1 ratio to receive MET-4 in addition to anti-PD1 antibody +/- anti-CTLA4 antibody as per SOC or control group. Patients will be stratified per BRAF mutation status. Subjects will be administered the same MET-4 dose as subjects in groups A, B and C. MET-4 will be initiated as run-in for a minimum of 1 week, and maximum of 2 weeks before ICI administration. MET-4 will be continued until unacceptable toxicity, confirmed PD by RECIST v1.1 or completion of 1 year of ICI, whichever occurs earlier. Subjects in the control arms of groups B, C and D will be treated with ICI therapy as per institution standard of care without MET-4.

Microbial Ecosystem Therapeutics (MET) is a new treatment approach developed as an alternative to fecal transplantation. Unlike donor stool used in fecal transplants, which are incompletely characterised complex communities of microbes and associated metabolites and fecal material, MET consists of a defined mixture of pure live cultures of intestinal bacteria isolated from a stool sample of a healthy donor.

MET-4

Lillian Siu, MD

Anna Spreafico, MD

This study is designed to assess the safety, tolerability and engraftment (cumulative relative abundance) of MET-4 strains when given in combination with immune checkpoint inhibitors (ICIs). There will be a safety cohort (group A) of 5 subjects which will receive MET-4 in addition to standard of care (SOC) ICI. After the safety cohort, 40 patients will be enrolled in group B which will be randomized to MET4 with SOC ICI vs. control group with SOC ICI only. Group C will enroll 20 patients who have already started on SOC ICI and have had first unconfirmed progression of disease and expected to continue with standard ICI treatment. These patients will be randomized to continue receiving standard ICI alone, or SOC ICI with MET4.

Human associated microorganisms (the microbiota) inhabit virtually all surfaces of the human body. The gut is densely colonized by the microbiota which aids in the digestion. Animal and human observational and experimental evidence show a link between gut microbiota and the activation, regulation and function of the immune system. Pre-clinical studies in mouse models have linked the gut microbiota to efficacy of anticancer therapies. Microbial Ecosystem Therapeutics (MET) is a new treatment approach developed as an alternative to fecal transplantation. MET consists of a defined mixture of pure live cultures of intestinal bacteria isolated from a stool sample of a healthy donor.

This study is designed to assess the safety, tolerability and engraftment (cumulative relative abundance) of MET-4 strains when given in combination with immune checkpoint inhibitors (ICIs).

Feasibility Study of Microbial Ecosystem Therapeutics (MET-4) to Evaluate Effects of Fecal Microbiome in Patients on ImmunOtherapy

Feasibility Study of Microbial Ecosystem Therapeutics (MET-4) to Evaluate Effects of Fecal Microbiome in Patients on ImmunOtherapy (MET4-IO)

Objective response rates of ICI when given in combination with MET-4 as measured per RECIST v1.1 and iRECIST

Time from randomization until disease progression or death as measured per RECIST v.1.1 and iRECIST

Flow cytometry/CyTOF of blood at baseline, 6-8 weeks post first dose of MET, 24 weeks post first dose

Standard immunohistochemistry (IHC) of baseline archival tumor

Flow cytometry/CyTOF of blood at baseline, week 3-4 post first dose of MET, and week 24 post first dose, and stool microbiome gene profiling at baseline, 10-16 days first dose of MET, week 3-4 post first dose, week 24 post first dose and end of treatment.

Fecal microbial abundance measured via qPCR and Nanostring analysis of stool at approximately day 12

Microbiome gene sequencing of stool at baseline and approximately day 12 post first dose

Related toxicities and severity collected as per CTCAE version 5.0

Fecal microbial abundance measured via qPCR and Nanostring analysis of stool at baseline and week 24 after first dose and EOT.

Microbiome gene sequencing of stool at baseline and week 24 after first dose and EOT.

Microbiome gene sequencing of stool at baseline, day 10-16 post first dose, week 3-4 post first dose, and week 24 after first dose and EOT.

NuBiyota

University Health Network, Toronto

Drug

Nicolas Isambert, Dr

The experimental plan will consist in:

The dose-finding Bayesian adaptive phase I portion of the study is designed to determine the optimal and recommended dose of IPP-204106N using a Bayesian "with memory" design with combined toxicity and pharmacokinetic endpoints to determine doses for successive cohorts of three patients. The Bayesian methodology allows updating information as the trial progresses and stopping the trial as soon as the information obtained is deemed to be sufficient. Preclinical toxicokinetic studies of N6L and IPP-204106N in dogs and the first phase I clinical trial with N6L will be used to inform the prior distribution in the present study.

The decisional part, according to the results of the phase I portion of the study, will define the optimal dose recommended for the phase IIa portion of the study.

The phase IIa portion of the study will confirm the optimal dose, and is designed to evaluate the safety and the preliminary efficacy of IPP-204106N in an expanded patient population treated at the recommended dose of IPP-204106N.

Dose-finding Adaptive Phase I/IIa Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of IPP-204106N on Advanced Solid Tumors

A Non-randomized, Open-label, Multi-centric Dose-finding Adaptive Phase I/IIa Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of Repeated Intravenous IPP-204106N Administrations in Adult Patients With Advanced Solid Tumors

Toxicity assessed during cycle 1 (until day 12): number of patients experiencing a dose limiting toxicity (DLT) according to the NCI-CTCAE (v 4.0, May 2009), defined as:

* Hematological drug-related toxicity: grade 4 neutropenia ≥7 days, grade 4 thrombocytopenia, grade 3 thrombocytopenia with hemorrhage/bleeding, and febrile neutropenia.
* Nausea, vomiting or diarrhea grade ≥3 despite optimal treatment.
* Any other drug-related biological or clinical grade ≥3 toxicity.

Plasma exposure assessed during cycle 1 (on day 1): number of patients reaching targeted plasma drug exposure, i.e. plasma N6L concentration ≥5 µM for at least two hours. This concentration corresponds to active concentration in vitro in human tumor cell lines.

Each patient's best objective response will be determined. The categories for best objective response are CR, PR, SD, PD or NE.

Analysis of time to progression (TTP) will be performed using in the ITT population using non-parametric method of Kaplan Meier and survival curves (PROC LIFETEST with SAS® software).

Genomic and/or proteomic biomarkers analyses may be performed as exploratory analyses, to identify the patients who, based on their individual tumor signature, will be most likely to respond and benefit from IPP-204106N therapy, and will be detailed in a further statistical analysis plan.

The duration of overall response is measured from the time measurement criteria are first met for CR or PR (whichever is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference for progressive disease the smallest measurements recorded on study).

Stable disease is measured from the start of the treatment until the criteria for progression are met, taking as reference the smallest summon study (if the baseline sum is the smallest, this is the reference for calculation of PD).

Analysis of progression-free survival (PFS) will be performed using in the ITT population using non-parametric method of Kaplan Meier and survival curves.

The tumor GR analyses may be performed as exploratory analyses

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety and Effectiveness of ABM-168 in Adults With Advanced Solid Tumors.	NCT05831995	Advanced Solid ... RAS Mutation RAF Mutation NF1 Mutation	ABM-168	18 Years -	ABM Therapeutics Corporation
Phase I/II Study of Capecitabine Plus Aflibercept to Treat Metastatic Colorectal Cancer	NCT01661972	Metastatic Colo...	Capecitabine an...	18 Years -	Duke University
Feasibility Study of Microbial Ecosystem Therapeutics (MET-4) to Evaluate Effects of Fecal Microbiome in Patients on ImmunOtherapy	NCT03686202	All Solid Tumor...	MET-4	18 Years -	University Health Network, Toronto
Dose-finding Adaptive Phase I/IIa Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of IPP-204106N on Advanced Solid Tumors	NCT01711398	All Solid Tumor...	Drug	18 Years -	Elro Pharma
Safety and Effectiveness of ABM-168 in Adults With Advanced Solid Tumors.	NCT05831995	Advanced Solid ... RAS Mutation RAF Mutation NF1 Mutation	ABM-168	18 Years -	ABM Therapeutics Corporation
Phase I/II Study of Capecitabine Plus Aflibercept to Treat Metastatic Colorectal Cancer	NCT01661972	Metastatic Colo...	Capecitabine an...	18 Years -	Duke University
Dose-finding Adaptive Phase I/IIa Study to Assess Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of IPP-204106N on Advanced Solid Tumors	NCT01711398	All Solid Tumor...	Drug	18 Years -	Elro Pharma

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