Neoplasms

Skin and Connective Tissue Diseases

All Conditions

Breast Neoplasms

Breast Diseases

Skin Diseases

All Drugs and Chemicals

Antineoplastic Agents

Hormones

Fulvestrant

Mitogens

Antineoplastic Agents, Hormonal

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Participants who are endocrine therapy pre-treated will be administrated at escalating doses orally of HS-10352 in combination with fulvestrant (500 mg, intramuscular).

Participants who are endocrine therapy-resistant will be treated with HS-10352 orally at the MTD/MAD identified in Stage 1 or/and lower dose in combination with fulvestrant (500 mg, intramuscular)

Participants who are endocrine therapy-sensitive or naïve will be treated with HS-10352 orally at MTD/MAD or/and lower dose identified in Stage 1 in combination with fulvestrant (500 mg, intramuscular)

Drug: HS-10352 HS-10352 will be administered at escalating doses orally once daily on a continuous dosing schedule starting on Cycle 1 Day 1 (C1D1) in a 28 day cycle.

Drug: Fulvestrant Fulvestrant is administered at a dose of 500 mg intramuscular on Cycle 1 Day 1, Day 15, and Day 1 of every cycle thereafter (where a cycle is 28 days).

HS-10352 combined with fulvestrant (Stage 1)

Drug: HS-10352 participants will be enrolled into Cohort 2 (endocrine therapy-resistant) and Cohort 3 (endocrine therapy-sensitive or naïve) respectively and HS-10352 will be administered at the recommended dose identified in Part 1.

Drug: Fulvestrant Fulvestrant is administered at a dose of 500 mg intramuscular on Cycle 1 Day 1, Day 15, and Day 1 of every cycle thereafter (where a cycle is 28 days).

HS-10352 combined with fulvestrant (Stage 2)

Xichun Hu, PhD

Jian Zhang, PhD

HS-10352 is a highly potent and selective small molecule inhibitor of phosphoinositide 3-kinase (p110α). The purpose of this study is to assess the safety, tolerability, pharmacokinetics (PK), and efficacy of HS-10352 plus fulvestrant in patients with hormone receptor (HR) positive, human epidermal growth factor 2 (HER2)-negative, advanced breast cancer (ABC) harboring PIK3CA mutations.

This is a Phase Ib open-label, 2-Part, multi-center study in China. The study will be conducted in two stages: Stage 1 is the dose-escalation part, which is designed to evaluate the safety, tolerability, PK and efficacy, as well as to determine the maximum tolerable dosage (MTD) or maximum applicable dose (MAD) of HS-10352 in combination with fulvestrant. Stage 2 is the dose-expansion part, which is aimed to further assess the efficacy, safety, tolerability and PK, and to establish the recommended phase 2 dose (RP2D) of HS-10352 in combination with fulvestrant.

All participants will be carefully monitored for adverse events (AE) during the study treatment and for 28 days after the last dose of study drug. The PK characteristics of HS-10352 and fulvestrant will be evaluated from C1 to C6. Subjects of this study will be assessed for progression once every 8 weeks until objective disease progression or withdrawal from the trial. As the disease progresses, survival follow-up is recommended bimonthly.

A Phase Ib Study of HS-10352 Plus Fulvestrant in Patients With Advanced Breast Cancer

A Phase Ib, Open-label, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of HS-10352 in Combination With Fulvestrant in Patients With Hormone Receptor (HR) Positive, Human Epidermal Growth Factor 2 (HER2)-Negative, PIK3CA Mutation, Locally Advanced or Metastatic Breast Cancer

MTD is defined as the previous dose level at which 2 or more out of 2\~6 subjects experienced a DLT.

MAD is defined as follows: a) based on PK data, it is anticipated that at this dose level, the dose-exposure plateau has been reached, b) based on existing safety data, it is judged that dose escalation following this dose level will have a large safety risk or subject intolerance, or c) based on the PK-PD model, it suggested that the optimal target concentration of safety and efficacy has been explored.

ORR is defined as the proportion of participants with best overall response (BOR) of confirmed complete response (CR) or confirmed partial response (PR) based on assessment per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST v1.1).

Assessed by number and severity of adverse events as evaluated according to NCI CTCAE v5.0.

Defines as the maximum plasma drug concentration of HS-10352

Defines as the maximum plasma drug concentration of fulvestrant

Defined as the time to reach maximum plasma concentration following drug administration of HS-10352

Defined as the time to reach maximum plasma concentration following drug administration of fulvestrant

Defines as the time measured for the concentration to decrease by one half.

Defines as area under the plasma concentration versus time curve from time zero to the 24-hour sampling time.

Defines as area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLOQ).

Defines as the maximum plasma drug concentration of HS-10352 at steady-state

Defines as the maximum plasma drug concentration of fulvestrant at steady-state

Defined as the time to reach maximum plasma concentration following drug administration of HS-10352 at steady-state

Defined as the time to reach maximum plasma concentration following drug administration of fulvestrant at steady-state

Defines as the minimum plasma drug concentration of HS-10352 at steady-state

Defines as the minimum plasma drug concentration of fulvestrant at steady-state

ORR is defined as the proportion of participants with BOR of confirmed CR or confirmed PR based on assessment per RECIST v1.1.

The disease control was deﬁned as the percentage of patients who have a best overall response (confirmed CR, PR, or stable disease for at least 6 weeks).

DOR only applies to participants whose best overall response is CR or PR based on assessment per RECIST v1.1. The start date is the date of first documented response of CR or PR (i.e. the start date of observed response, not the date when response was confirmed), and the end date is defined as the date of the first documented progression or death due to underlying cancer.

PFS is defined as the time from the date of randomization or first dose (if randomization is not needed) to the date of the first documented progression or death due to any cause. PFS will be assessed per RECIST v1.1.

OS is defined as the time from the date of randomization or first dose (if randomization is not needed) to the date of death due to any cause. For each participant who is not known to have died as of the cutoff date for overall survival analysis, OS time was censored on the last date the participant is known to be alive.

Jiangsu Hansoh Pharmaceutical Co., Ltd.

Digestive System Diseases

Colorectal Neoplasms

Intestinal Neoplasms

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Capecitabine

Antimetabolites

A phase lb/ll, open label, single arm study with Alpelisib plus Capecitabine in patients with PIK3CA mutant metastatic colorectal cancer

Adding Alpelisib to Capecitabine as a salvage regimen in mCRC with PIK3CA mutation

Alpelisib plus Capecitabine combination

Soohyeon Lee, MD

The investigator assesses the efficacy and safety of alpelisib and capecitabine in patients with PIK3CA mutant metastatic colorectal cancer who failed two prior standard chemotherapies.

Phase lb To determine maximal tolerated dose (MTD) and recommended phase ll dose (RP2D) of alpelisib in combination with capecitabine regardless of PIK3CA mutation of any solid tumors

Phase ll To investigate the progression-free survival (PFS)

Conduct the exploratory biomarker analysis for efficacy and resistance of alpelisib plus capecitabine combination (using collected clinical samples)

A phase lb/ll, open label, single arm study

Alpelisib and Capecitabine in Patients With PIK3CA Mutant mCRC Patients

A Phase lb/ll, Open Label, Single Arm Study to Assess Efficacy and Safety of Alpelisib and Capecitabine in Patients With PIK3CA Mutant Metastatic Colorectal Cancer Who Failed Two Prior Standard Chemotherapies

Maxiaml Tolerable Dose and Recommended Phase 2 Dose of combination Maximal tolerable dose and random phase 2 dose confirmation in Alpelisib with Capecitabine in phase 1b

Korean Cancer Study Group

Assistant Professor

Diseases and Abnormalities at or Before Birth

Adenomatous Polyposis Coli

APC, TP53, PIK3CA, KRAS APC, TP53, PIK3CA, MLH1 APC, TP53, PIK3CA, KRAS, and MLH1 APC, TP53, PIK3CA

co-occuring mutation

This is a pathogenic mutation profile of colorectal patients specifically in 5 genes, i.e. APC, TP53, PIK3CA, KRAS, and MLH1. Single nucleotide variants identified were synchronized with patients' characteristics.

Patogenic Mutation in 5 Genes

Genomic Landscape of APC, KRAS, TP53, PIK3CA, and MLH1 in Colorectal

grade, stage, lymphovascular invasion, tumor location

Dr Cipto Mangunkusumo General Hospital

Principal Investigator - Staff of Digestive Division - General Surgery Department

Estrogen Receptor Modulators

Following the single agent dose escalation (Part A), additional patients with mutations in the PIK3CA gene will be enrolled to a single agent dose expansion phase at the MTD or recommended phase II dose (RP2D) at the selected dose schedule (as appropriate) to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected dose (Part B). Part B will include patients with ER+/HER2 negative breast cancer whose tumours have a mutation of the PIK3CA gene and patients with any solid tumours which have a mutation of the PIK3CA gene.

AZD8835 in combination with fulvestrant dose escalation

Following the combination dose escalation segment of the study (Part C), additional postmenopausal patients with ER+/HER negative breast cancer and mutations of the PIK3CA gene will be enrolled to a AZD8835 and fulvestrant combination dose expansion phase at the maximum tolerated dose (MTD) or recommended phase II dose (RP2D) (as appropriate) to explore further the safety, tolerability, pharmacokinetics and biological activity at the selected dose (Part D).

AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components

AZD8835

AZD 8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components

AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components. Fulvestrant is approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer following progression of disease while receiving anti-estrogen therapy.

AZD8835 in combination with fulvestrant

AZD8835 is a small molecule that inhibits cancer progression by blocking PI3 kinase pathway components. Fulvestrant is approved for the treatment of postmenopausal women with ER+ locally advanced or metastatic breast cancer following progression of disease while receiving anti-estrogen therapy

Hendrik-Tobias Arkenau, FRCP, PhD

First time in patients study of AZD8835. The study has four parts. Part A AZD8835 is administered as a single agent in a multiple ascending dose escalation phase to investigate dose level for monotherapy. Part B follows the multiple ascending dose phase, additional patients with tumors with documented PIK3CA gene mutation will be enrolled to a single dose expansion phase. Part C is a second dose escalation phase in which post-menopausal patients with estrogen receptor positive (ER+), HER2 negative breast cancer will receive AZD8835 in combination with fulvestrant. Part D follows the combination dose escalation phase of the study, additional postmenopausal patients with ER+/HER2 negative breast cancer with documented PIK3CA gene mutation will be enrolled to a AZD8835 and fulvestrant combination dose-expansion phase at maximum tolerated dose or recommended phase II dose.

AZD8835 is a novel small molecule that inhibits cancer progression by blocking PI3 kinase pathway components p110α and p110δ.

In this first-time-in-patient study, AZD8835 will initially be administered as a single agent to patients with advanced solid malignancies. Patients will be treated at a starting dose of 20 mg twice daily (BID), administered weekly on Days 1 and 4 and will be escalated to reach a maximum-tolerated dose (MTD) in patients as defined by dose-limiting toxicities (DLTs). A BID intermittent dosing schedule administered weekly on Days 1 and 4 of an oral formulation of AZD8835 will be used, as deemed optimal and effective in non-clinical studies, primarily to determine the safety and tolerability of AZD8835. The pharmacokinetics (PK) of AZD8835 and potential biological activity will also be investigated. In Part A of this study, AZD8835 will be administered as a single agent in a multiple ascending dose escalation phase to investigate the appropriate monotherapy dose level for clinical use. Additional dosing schedules may be studies, including dosing on Days 1 and 2 of each week, rather than Days 1 and 4.

Backfilled pharmacodynamic (PDc) cohorts in selected patients with tumours that have documented mutations in the phosphatidylinositol-4,5- bisphosphate 3-kinase, catalytic subunit alpha (PIK3CA) gene will allow further preliminary assessment of the biological effect of AZD8835 in these patients.

Following the single-agent dose-escalation phase of the study, additional patients with tumours that have documented mutations in the PIK3CA gene will be enrolled to a single-agent dose-expansion phase at the MTD or recommended Phase II dose (RP2D) at the selected dose schedule (as appropriate) to explore further the safety, tolerability, PK, and biological activity at the selected dose (Part B).

In addition, a further dose-escalation phase will be initiated following the observation of specific pre-determined criteria in the single-agent dose escalation, in which postmenopausal patients with oestrogen receptor positive (ER+), HER2 negative breast cancer will receive AZD8835 in combination with fulvestrant (Part C). The combination dose-escalation phase will investigate the appropriate combination dose level for clinical use.

Following the combination dose-escalation phase of the study, additional postmenopausal patients with ER+ breast cancer and tumours with documented mutations of the PIK3CA gene will be enrolled to a AZD8835 and fulvestrant combination dose-expansion phase at the MTD or RP2D (as appropriate) to explore further the safety, tolerability, PK, and biological activity at the selected dose (Part D).

Phase I, Dose Study to Look at the Safety and Pharmacokinetics of AZD8835 in Patients With Advanced Solid Tumours

A Phase I, Open-Label, Multicentre, Dose-Escalation Study to Investigate the Safety and Pharmacokinetics of AZD8835 in Patients With Advanced Solid Tumours

MTD - A dose will be considered non-tolerated and dose escalation will stop if 2 or more of up to 6 evaluable patients experience a dose limiting toxicity at a dose level. Once the non-tolerated dose is defined, the MTD will be confirmed at the previous dose level below the non-tolerated dose or a dose between the non-tolerated dose and the last tolerated dose my be investigated. A minimum of 6 evaluable patients are required to determine the MTD. Recommended Phase II dose - A minimum of 6 evaluable patients is necessary to determine the recommended dose. A dose will be considered non-tolerated and dose escalation will stop if 2 or more patients experience a dose dose limiting toxicity at a dose level.

Assessed in terms of adverse events and laboratory data that is collected on all patients

Venous blood samples (2 mL) for determination of concentrations of AZD8835 and the investigation of AZ8835 metabolites in plasma will be taken during Parts A, B, C, D

Categorization of objective tumor response will be based on RECIST v1.1 guidelines for complete response, partial response, stable disease, or progression of disease

Tumor samples will be analyzed to assess PRAS40 phosphorylation, AKT phosphorylation, S6 phosphorylation, FOXO3a localisation

AstraZeneca

Participants will receive single dose of HS-10352 on Day 1 of Cycle 1 followed by once daily from Day 8 of Cycle 1. (Cycle length: 35 days for Cycle 1 and 28 days for all other cycles). Participants will continue treatment until the end of the study in the absence of unacceptable toxicities and unequivocal disease progression.

HS-10352

Xichun Hu

Herui Yao

Jian zhang

HS-10352 is a highly potent and selective small molecule inhibitor of phosphoinositide 3-kinase (p110α). In preclinical studies, it demonstrated strong activity against PI3K p110α in vitro and in vivo, and inhibited tumor cell growth. The first-in-human trial is conducted to assess the maximum tolerated dose (MTD) and dose limiting toxicity (DLT), to evaluate the pharmacokinetics, safety and preliminary anti-tumor activity of HS-10352 at single dose and multiple doses.

This is a phase I, open-label, multicenter study to evaluate safety, tolerability, pharmacokinetics, and efficacy of single and multiple doses of oral administration of HS-10352 in patients with locally advanced or metastatic breast cancer with hormone receptor (HR) positive and epidermal growth factor receptor 2 (HER2) negative who have progressed following prior therapy. There is a dose-escalation study, which is designed to evaluate the safety, tolerability, and pharmacokinetics of single dose and multiple doses of HS-10352 given once every day (QD). An alternative dosing schedule of twice every day (BID) may be investigated if the drug clearance of HS-10352 is faster than anticipated.

All patients will be carefully followed for adverse events during the study treatment and for 28 days after the last dose of study drug. Subjects of this study will be permitted to continue therapy with assessments for progression once every 8 weeks, if the product is well tolerated and the subject has stable disease or better. As the disease progresses, survival follow-up is recommended bimonthly.

Phase I Study of the HS-10352 in Patients With Advanced Breast Cancer

A Phase 1, Open-label, Multicenter Study to Evaluate Safety, Tolerability, Pharmacokinetics, and Efficacy of Single and Multiple Doses of Oral Administration of HS-10352 in Patients With Locally Advanced or Metastatic Breast Cancer Progressing After Standard Therapy

DLT is defined as one of the following HS-10352 related adverse event (AE) that occurs during the DLT period, excluding AE assessed by investigator exclusively related to subject's underlying disease or medical condition (graded according to the NCI Common Terminology Criteria for Adverse Events (CTCAE), Version 5.0):

MTD was defined as the previous dose level at which 2 of 2 subjects or 2 out of 6 subjects experienced a DLT.

Assessed by number and severity of adverse events as recorded on the case report form, vital signs, laboratory variables, physical examination, electrocardiogram, RECIST1.1, and NCI CTCAE v5.0.

In the study of single-dose, Cmax will be obtained following administration of a single oral dose of HS-10352 on Day 1 to Day 6.

At multiple-dose, Cmax ss will be obtained on Day 1 of dosing in the second 28-Day cycle of therapy.

In the study of single-dose, Tmax will be obtained following administration of a single oral dose of HS-10352 on Day 1 to Day 6.

At multiple-dose, Tmax will be obtained on Day 1 of dosing in the second 28-Day cycle of therapy.

Apparent terminal half-life is the time measured for the concentration to decrease by one half. Terminal half-life calculated by natural log 2 divided by λz.

Area under the plasma concentration versus time curve from time zero to the 24-hour sampling time at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-24 was to be calculated according to the mixed log-linear trapezoidal rule.

Area under the plasma concentration versus time curve from time zero to the last sampling time t at which the concentration was at or above the lower limit of quantification (LLQ). AUC0-t was to be calculated according to the mixed log-linear trapezoidal rule.

AUC0-∞ was calculated by combining AUC0-t and AUCextra. AUCextra represents an extrapolated value obtained by Clast/ λz, where Clast is the calculated plasma concentration at the last sampling time point at which the measured plasma concentration is at or above the LLQ and λz is the apparent terminal rate constant determined by log-linear regression analysis of the measured plasma concentrations of the terminal log-linear phase.

Anti-tumor efficacy will be assessed by best radiographic response based on Response Evaluation Criteria in Solid Tumors at baseline (Day -28 to -1). For patients that continue on repeating 28-Day cycles after the primary evaluation period, progression will be assessed after each 8 weeks of therapy. ORR is defined as the percentage of patients with a complete response (CR) or partial response (PR) that was confirmed at a subsequent scan at least 4 weeks later, as assessed according to RECIST version 1.1.

Objective response was assessed by RECIST 1.1 thereby to evaluate disease control rate. Disease control was deﬁned as the percentage of patients who have a best overall response (confirmed CR, PR, or stable disease for at least 6 weeks).

Objective response was assessed by RECIST 1.1 thereby to evaluate deepness of response. Depth of response was defined as the relative change in the sum of the longest diameters of RECIST target lesions at the nadir in the absence of new lesions, or progression of non-target lesions compared with baseline.

Progression of tumor was assessed by RECIST 1.1 thereby to evaluate progression free survival. Progression-free survival was deﬁned as the time from date of ﬁrst dose until the documentation of objective disease progression (PD) or death from any cause in the absence of progression (whichever occurred first), regardless of whether they subsequently received non-study anti-cancer therapy.

Overall survival was deﬁned as the time from date of ﬁrst dose until the documentation of death from any cause.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase Ib Study of HS-10352 Plus Fulvestrant in Patients With Advanced Breast Cancer	NCT05504213	Breast Cancer	HS-10352 combin... HS-10352 combin...	18 Years -	Jiangsu Hansoh Pharmaceutical Co., Ltd.
Alpelisib and Capecitabine in Patients With PIK3CA Mutant mCRC Patients	NCT04753203	Metastatic Colo... PIK3CA Gene Mut...	Alpelisib plus ...	19 Years - 90 Years	Korean Cancer Study Group
Patogenic Mutation in 5 Genes	NCT04976439	Colorectal Canc... APC Gene Mutati... TP53 Gene Mutat... PIK3CA Gene Mut... KRAS Mutation-R... MLH1 Gene Mutat...	co-occuring mut...	18 Years -	Dr Cipto Mangunkusumo General Hospital
Patogenic Mutation in 5 Genes	NCT04976439	Colorectal Canc... APC Gene Mutati... TP53 Gene Mutat... PIK3CA Gene Mut... KRAS Mutation-R... MLH1 Gene Mutat...	co-occuring mut...	18 Years -	Dr Cipto Mangunkusumo General Hospital
Phase I, Dose Study to Look at the Safety and Pharmacokinetics of AZD8835 in Patients With Advanced Solid Tumours	NCT02260661	Advanced Solid ... Breast Cancer -... Breast Cancer -...	AZD8835 AZD8835 AZD8835 in comb... AZD8835 in comb...	18 Years - 130 Years	AstraZeneca
A Phase Ib Study of HS-10352 Plus Fulvestrant in Patients With Advanced Breast Cancer	NCT05504213	Breast Cancer	HS-10352 combin... HS-10352 combin...	18 Years -	Jiangsu Hansoh Pharmaceutical Co., Ltd.
Patogenic Mutation in 5 Genes	NCT04976439	Colorectal Canc... APC Gene Mutati... TP53 Gene Mutat... PIK3CA Gene Mut... KRAS Mutation-R... MLH1 Gene Mutat...	co-occuring mut...	18 Years -	Dr Cipto Mangunkusumo General Hospital
Phase I Study of the HS-10352 in Patients With Advanced Breast Cancer	NCT04631835	Breast Cancer	HS-10352	18 Years - 75 Years	Jiangsu Hansoh Pharmaceutical Co., Ltd.
Phase I Study of the HS-10352 in Patients With Advanced Breast Cancer	NCT04631835	Breast Cancer	HS-10352	18 Years - 75 Years	Jiangsu Hansoh Pharmaceutical Co., Ltd.

Spots Global Cancer Trial Database for pik3ca gene mutation