Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

Fibrinolytic Agents

All Drugs and Chemicals

Snake venom protein C activator

ARV-471 administered orally QD continuously and Samuraciclib administered orally QD continuously on 28-day cycles

Daily oral dosages of ARV-471 continuously, dose escalation/de-escalation in Phase 1b until RP2D determined, cycles lasting 28 days

vepdegestrant

Daily oral dosages of Samuraciclib continuously, dose escalation/de-escalation in Phase 1b until RP2D determined, cycles lasting 28 days

Samuraciclib

Pfizer CT.gov Call Center

The purpose of this study is to learn about the safety and effects of the study medicine called vepdegestrant. The safety and effects of vepdegestrant will be see when given with other medicines. Vepdegestrant is studied to see if it can be a possible treatment for advanced metastatic breast cancer. This type of cancer would have spread from where it started (breast) to other parts of the body and would be tough to treat.

The study is seeking for participants who have breast cancer that:

* is hard to treat (advanced) and may have spread to other organs (metastatic). is sensitive to hormonal therapy (it is called estrogen receptor positive).
* is no longer responding to treatments taken before starting this study.

This study is divided into separate sub-studies.

For Sub-Study C:

All the participants will receive vepdegestrant and a medicine called samuraciclib.

Vepdegestrant and samuraciclib will be taken once in a day by mouth. The medicines will be taken at home. The experience of people receiving the study medicines will be studied. This will help see if the study medicine is safe and effective.

Participant will continue to take vepdegestrant and samuraciclib until:

* their cancer is no longer responding, or
* side effects become too severe.

They will have visits at the study clinic about every 4 weeks.

C4891024 is a prospective, open-label, multicenter, Phase 1b/2 sub-study to evaluate the safety, antitumor activity, and PK of ARV-471 with samuraciclib in the treatment of participants with A/MBC. The sub-study is part of Umbrella platform, TACTIVE-U, comprising multiple sub-studies that independently evaluate ARV-471 in participants with Estrogen Receptor Positive/Human Epidermal Growth Factor Receptor 2 Negative (ER+/HER2-) Advanced or Metastatic Breast Cancer. ARV-471 will act as the backbone therapy given in combination with other anticancer agents thought to have clinical relevance in ER+ breast cancer.

Phase 1b will use an escalation/de-escalation approach to determine the RP2D of ARV-471 when administered in combination with samuraciclib. The decision to escalate the starting dose level of ARV-471 will be using mTPI-2 decision criteria based on the number of DLT-evaluable participants and the number of DLTs in those participants during the DLT observation period (Cycle 1).

Phase 2 will further evaluate the preliminary antitumor activity and safety of the combination RP2D.

In addition, the potential drug-drug interaction (DDI) between ARV-471 and samuraciclib will be evaluated, at the doses selected as recommended dose for expansion (RDE(s)), in a DDI Assessment Cohort(s)

TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer. (Sub-Study C)

TACTIVE-U: AN INTERVENTIONAL SAFETY AND EFFICACY PHASE 1B/2, OPEN-LABEL UMBRELLA STUDY TO INVESTIGATE TOLERABILITY, PK, AND ANTITUMOR ACTIVITY OF VEPDEGESTRANT (ARV-471/PF-07850327), AN ORAL PROTEOLYSIS TARGETING CHIMERA, IN COMBINATION WITH OTHER ANTICANCER TREATMENTS IN PARTICIPANTS AGED 18 AND OLDER WITH ER+ ADVANCED OR METASTATIC BREAST CANCER, SUB-STUDY C (ARV-471 IN COMBINATION WITH SAMURACICLIB)

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests.

Dose Limiting Toxicities rate for ARV-471 in combination with Samuraciclib, estimated based on data from DLT-evaluable participants during the DLT observation period (Cycle 1).

Steady-state Area under the plasma concentration versus time curve (AUCtau) of ARV-471 with and without coadministration of samuraciclib

Steady-state Peak Plasma concentration ( Cmax) of ARV-471 with and without coadministration of samuraciclib

Objective response (OR) refers to confirmed complete response (CR) or partial response (PR) according to Response Evaluation Criteria in Solid Tumor (RECIST) version 1.1. as determined by investigator assessment.

Single dose AUC0-72 of samuraciclib with and without coadministration of ARV 471.

Single dose Cmax of samuraciclib with and without coadministration of ARV 471.

AEs as characterized by type, frequency, intensity as graded by NCI CTCAE version 5.0, timing, seriousness, and relationship to ARV-471 in combination with samuraciclib.

Laboratory test abnormalities as characterized by type, frequency, intensity (as graded by NCI CTCAE version 5.0), and timing.

Changes from baseline for the ECG parameters heart rate, QTcF, PR interval, and QRS complex will be summarized by treatment and time. The frequency of uncorrected QT values above 500 ms will be tabulated.

Duration of Response (DoR) is defined for participants with confirmed OR (CR or PR) as the time from the first documentation of OR to the first documentation of objective tumor progression or to death due to any cause, whichever occurs first.

Clinical Benefit Response (CBR) is defined as the proportion of participants with Best Overall Response of confirmed CR or PR at any time, or Stable Disease (SD) ≥24 weeks

Progression Free Survival (PFS) is defined as the time from the date of first dose of study interventions to the date of first documentation of PD or death due to any cause, whichever occurs first.

To evaluate the plasma exposure of ARV-471 and samuraciclib when ARV-471 and samuraciclib are given in combination.

AUCtau of ARV-471 with and without co-administration of samuraciclib

Cmax of ARV-471 with and without co-administration of samuraciclib

To assess changes from baseline levels in plasma ctDNA with treatment and to evaluate potential predictability of their associations with clinical outcomes.

Participants classified on basis of pathological TP53 mutation detected or not detected.

Overall Survival (OS) is defined as the time from the date of first dose of study interventions to the date of death due to any cause

Arvinas Estrogen Receptor, Inc.

Carrick Therapeutics Limited

Pfizer

Digestive System Diseases

Gland and Hormone Related Diseases

Symptoms and General Pathology

Rare Diseases

Stomach Neoplasms

Carcinoma

Carcinoma, Squamous Cell

Pancreatic Neoplasms

Biliary Tract Neoplasms

Gastrointestinal Stromal Tumors

Neuroendocrine Tumors

Esophageal Squamous Cell Carcinoma

Neoplasms, Unknown Primary

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Neoplasms, Squamous Cell

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Esophageal Neoplasms

Head and Neck Neoplasms

Esophageal Diseases

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Biliary Tract Diseases

Neoplasm Metastasis

Neoplastic Processes

Stomach Cancer

Pancreatic Cancer

Neuroendocrine Tumor

Neuroepithelioma

Esophageal Cancer

Antineoplastic Agents

Angiogenesis Inhibitors

Poly(ADP-ribose) Polymerase Inhibitors

Enzyme Inhibitors

According to the treatment dose approved by NMPA/FDA, evaluation will be conducted every 2 cycles until tumor progression or adverse events cannot be tolerated.

FGFR Inhibitor, IDH1 Inhibitor, HER2 Inhibitor, PARP Inhibitor, BRAF Inhibitor, MEK Inhibitor, ICIs, EGFR-TKIs, NTRK-TKI, and et. al.

Patients will receive other treatments, including cytotoxic drugs, antiangiogenic drugs, best supportive care, clinical trials of unmatched new drugs, etc..

Other Therapy

Lin Shen, MD

Shen Lin, MD

Shen Lin, professor

This a prospective real-world navigation study using tumor DNA sequencing technology to sequence genes of previously treated and refractory gastrointestinal tumors, which are generally considered to be highly heterogeneous and complex, to screen potential molecular targeted drugs for individualized treatment. This study may provide feasibility and response information, which will be the basis for designing better randomized trials, which may change the pattern of cancer treatment. If the hypothesis is finally proved, it will help doctors and molecular biologists to choose the best drug (or combination of drugs) based on the individual oncogenomics of each patient.

This is a prospective, open label, real-world study to evaluate the feasibility of matched molecular targeted therapy in patients with refractory gastrointestinal cancer based on tumor molecular characteristics as standard treatment failure. This is a non-randomized trial designed to test molecular matching strategies based on patient genome information. The molecular tumor board (MTB) will recommend treatment, but the treatment decision is up to the attending physician. FoundationOne CDx was used for tissue genomic analysis. If possible, PD-L1 immunohistochemistry (IHC), tumor mutation load (TMB), and microsatellite instability (MSI) status will also be evaluated. Based on this information, MTB, composed of multidisciplinary experts, will focus on the selection of customized, best matched drugs or combinations to target most of the genomic changes in each patient, also taking into account potential drug toxicity. The final treatment will be based on the choice of oncologists, who will formulate treatment plan by combining MTB discussion, patient preference, attention to complications, consideration of drug toxicity, insurance coverage of off label drugs and availability of clinical trials of research drugs, thus reflecting the actual clinical practice nowadays in China. The acquisition of drugs follows the actual situation in the real world and is not within the scope of this study design.

The principles of MTB treatment recommendations can be referred to the NCI-MATCH trial:

Grade 1: FDA / NMPA approval; clear evidence and mechanism; concomitant diagnostic relationship between drug and target.

Grade 2: The drug reaches the clinical end point (objective response rate, PFS or OS); there is evidence of target inhibition; there is strong evidence to predict relationship between the target and the drug.

Grade 3: The drug has evidence of clinical activity and target inhibition; there is some evidence to predict the relationship between target and drug.

Grade 4: Pre-clinical evidence of anti-tumor activity and evidence of target inhibition; there is hypothesis to predict the relationship between target and drug.

Patients who meet the inclusion criteria and sign informed consent will be analyzed for tumor mutation by FoundationOne CDx detection. Biopsy specimens of metastatic foci can be selected for gene detection. If there is no targeted therapy among patients, the archived diagnostic tumor samples can also be used for detection. If the patient has received targeted therapy, the investigators will try to obtain biopsy samples after treatment. If the sample cannot be tested or the test results are not satisfactory, additional slices need to be sent to the laboratory. If the repeated test fails, repeat biopsy if the clinical conditions permit, or patients should be included in the unmatched treatment group.

Determining the interventability of gene mutations depends on genomic changes, allele frequency, and diagnosis. This study will combine the recommendations of MTB and gene testing reports to determine the interventability of mutated genes.

Interventional mutation: cancers have FDA or NMPA approved therapies, or there are matching drugs in clinical trials.

Non-interventional mutation: there is no FDA or NMPA approved treatment for cancers, and no matching drug is available in clinical trials.

MTB should at least be composed of attending doctors, molecular pathology experts and bioinformatics experts. The research center is responsible for the establishment and holding of MTB. As management of patients enrolled in this study is essential, the research committee, including but not limited to the main investigator of the study and the treated medical oncologist, can provide advice as needed between MTB meetings to avoid treatment delays. By analyzing the genomic variation of patients, independent MTB recommends molecular targeted therapy that can inhibit the mutation directly or through related pathways or be included in relevant clinical trials. The independent research committee will use the "N-to-1" model of precision medicine to propose a matching therapy consisting of at least one drug that targets molecular changes. The investigators expect 50-70% of patients to carry intervening variants, and that proportion is rising rapidly as learning more about these pathways and drugs. The investigators expect that about 40% of patients with intervening variants will be able to receive molecular targeted "matching" therapy.

Targeted Agent Evaluation in Digestive Cancers in China Based on Molecular Characteristics

A Real-world Study to Explore and Evaluate Individualized Targeted Agents for Patients of Digestive Cancers Based on Molecular Characteristics After Standard Therapy Failure in China

Objective response rate (ORR) per RECIST 1.1 criteria according to investigators assessment

Proportion of patients with intervening genomic variation

Progression Free Survival (PFS) per RECIST 1.1 criteria according to investigators assessment

Overall Survival (OS) per RECIST 1.1 criteria according to investigators assessment

Number of participants with treatment-related adverse events as assessed by CTCAE v5.0

Differences of OS between 2 groups per RECIST 1.1 criteria according to investigators assessment

Hangzhou DIAN Medical Diagnostic Center Co., Ltd., China

Peking University

Professor

ARV-471 administered orally once daily (QD) and Abemaciclib orally twice daily (BID) on 28-day cycle

Daily oral dosages of ARV-471 continuously, dose escalation/de-escalation in Phase 1b until the recommended phase 2 dose (RP2D) determined, cycles lasting 28 days

ARV-471

Daily oral dosages of Abemaciclib continuously, cycles lasting 28 days

Abemaciclib

The purpose of this clinical trial is to learn about the safety and effects of the study medicine (called ARV-471) when given together with other medicines for the potential treatment of advanced or metastatic breast cancer.

This study is seeking participants who have breast cancer that:

* is advanced, may have spread to other organs (metastatic) and cannot be fully treated by surgery or radiation therapy
* is sensitive to hormonal therapy (it is called estrogen receptor positive); and
* is no longer responding to previous treatments This study is divided into separate sub-studies.

For Sub-Study A:

All participants will receive ARV-471 and a medicine called abemaciclib. ARV-471 will be given by mouth, at home, 1 time a day. Abemaciclib will be given by mouth, at home, 2 times a day. We will examine the experiences of people receiving the study medicines. This will help us determine if the study medicines are safe and effective.

Participants will continue to take ARV-471 and abemaciclib until their cancer is no longer responding, or side effects become too severe. They will have visits at the study clinic about every 4 weeks.

C4891006 is a sub-study from the Umbrella platform, TACTIVE-U, comprising multiple sub-studies that independently evaluate ARV-471 in participants with Estrogen Receptor Positive (ER+) Advanced or Metastatic Breast Cancer (A/MBC). ARV-471 will act as the backbone therapy given in combination with other anticancer agents thought to have clinical relevance in ER+ breast cancer.

Phase 1b will use an escalation/de-escalation approach to determine the RP2D of ARV-471 when administered in combination with abemaciclib. The decision to de-escalate the starting dose levels of ARV 471 will be using mTPI-2 decision criteria based on the number of DLT-evaluable participants and the number of DLTs in those participants during the DLT observation period (Cycle 1 \[first 28 days\]).

Phase 2 will further evaluate the preliminary antitumor activity and safety of the combination RP2D.

TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer (Sub-Study A)

TACTIVE-U: An Interventional Safety and Efficacy Phase 1b/2, Open-label Umbrella Study to Investigate Tolerability, pk, and Antitumor Activity of Vepdegestrant (ARV-471/PF-07850327), an Oral Proteolysis Targeting Chimera, in Combination With Other Anticancer Treatments in Participants Aged 18 Years and Over With ER+ Advanced or Metastatic Breast Cancer, Sub-study A (ARV-471 in Combination With Abemaciclib)

Dose Limiting Toxicities rate for ARV-471 in combination with abemaciclib, estimated based on data from DLT-evaluable participants during the DLT observation period (Cycle 1 \[28 days\]).

An adverse event (AE) were any untoward medical occurrence in a participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. An SAE is any untoward medical occurrence that, at any dose: resulted in death; required inpatient hospitalization or prolongation of existing hospitalization; was life-threatening; resulted in persistent or significant disability/ incapacity; congenital anomaly/birth defect and other important medical events. Treatment-related AE is any untoward medical occurrence attributed to study drug in a participant who received study drug.

AEs were graded by the investigator according to the Common Terminology Criteria for Adverse Events (CTCAE version 5.0) and coded using MedDRA were reported. Grade 1=mild; Grade 2=moderate; Grade 3=severe and Grade 4=life-threatening or disabling and grade 5=death.

Blood samples were collected for the analysis of following hematology and coagulation parameters: hemoglobin \[g/L\], platelets, leukocytes, neutrophils, lymphocytes, monocytes, eosinophils and basophils \[10\^9/L\]; partial thromboplastin time prolonged, international normalized ratio increased, prothrombin time. Number of participants with hematological and coagulation abnormalities by grade as per CTCAE version 5.0 were reported. Grade 1=mild; Grade 2=moderate; Grade 3=severe and Grade 4=life-threatening or disabling and grade 5=death.

For laboratory tests without CTCAE grade definitions, results will be categorized as normal, abnormal, or not done.

Blood samples were collected for analysis of clinical chemistry parameters. These included: alanine aminotransferase, alkaline phosphatase, aspartate aminotransferase, \[international unit per liter (IU/L)\] ; Lipase and amilase \[IU/L\] (limited to cycle1 only); Albumin, bilirubin, urea ,calcium, creatinine, glucose, magnesium, phosphate, uric acid, chloride, potassium and sodium \[millimol per liter (mmol/L)\]; eGFR \[milliliter per minute (ml/min)\]. Number of participants with blood chemistry abnormalities by grade as per CTCAE version 5.0 were reported. Grade 1=mild; Grade 2=moderate; Grade 3=severe and Grade 4=life-threatening or disabling and grade 5=death.

For laboratory tests without CTCAE grade definitions, results will be categorized as normal, abnormal, or not done.

To assess changes from baseline levels in plasma circulating DNA (ctDNA) with treatment and to evaluate potential predictability of their associations with clinical outcome

Exposure (AUCtau) of abemaciclib with and without co-administration of ARV-471

Concentration (Cmax) of abemaciclib with and without co-administration of ARV-471

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer. (Sub-Study C)	NCT06125522	Breast Cancer	vepdegestrant Samuraciclib	18 Years -	Pfizer
TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer. (Sub-Study C)	NCT06125522	Breast Cancer	vepdegestrant Samuraciclib	18 Years -	Pfizer
Targeted Agent Evaluation in Digestive Cancers in China Based on Molecular Characteristics	NCT04584008	Biliary Tract N... Gastric Cancer Esophageal Squa... Colorectal Canc... Gastrointestina... Pancreatic Canc... Neuroendocrine ... Unknown Primary... Digestive Cance...	FGFR Inhibitor,... Other Therapy	18 Years -	Peking University
TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer. (Sub-Study C)	NCT06125522	Breast Cancer	vepdegestrant Samuraciclib	18 Years -	Pfizer
Targeted Agent Evaluation in Digestive Cancers in China Based on Molecular Characteristics	NCT04584008	Biliary Tract N... Gastric Cancer Esophageal Squa... Colorectal Canc... Gastrointestina... Pancreatic Canc... Neuroendocrine ... Unknown Primary... Digestive Cance...	FGFR Inhibitor,... Other Therapy	18 Years -	Peking University
TACTIVE-U: A Study to Learn About the Study Medicine (Vepdegestrant) When Given With Other Medicines in People With Advanced or Metastatic Breast Cancer (Sub-Study A)	NCT05548127	Breast Cancer	ARV-471 Abemaciclib	18 Years -	Pfizer

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