Neoplasms

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Neuroendocrine Tumors

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Neoplasms, Glandular and Epithelial

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Pancreatic Neuroendocrine Tumor

Neuroepithelioma

Antineoplastic Agents

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Gastrointestinal Agents

Anti-Infective Agents

Everolimus

Octreotide

Sirolimus

Temsirolimus

MTOR Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

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Immunologic Factors

Antineoplastic Agents, Hormonal

Stratum 1 patients who were not receiving regular Octreotide Depot therapy. These patients were to receive everolimus monotherapy at 10 mg/day.

Stratum 2 patients who were to receive everolimus 10 mg/day in addition to continuing their entry dose of Octreotide Depot therapy.

Patients were instructed to take two 5 mg tablets of everolimus orally with a glass of water, once daily (preferably in the morning). Dosing was strongly recommended to occur at the same time every day.

Participants took two 5 mg tablets of Everolimus orally with a glass of water, once daily (preferably in the morning) in a fasting state or after no more than a light, fat-free meal. Dosing was to occur at the same time each day. If vomiting occurred, the vomited dose was not to be replaced.

Everolimus 10 mg

Octreotide Depot

Novartis Pharmaceuticals

The purpose of this study was to assess the efficacy and safety of everolimus in the treatment of advanced pancreatic neuroendocrine tumor (NET) not responsive to cytotoxic chemotherapy. All patients were treated with everolimus until either tumor progression was documented using a standard criteria that measures tumor size called Response Evaluation Criteria in Solid tumors (RECIST), or until unacceptable toxicity occurred, or until the patient or investigator requested discontinuation of treatment.

This was a stratified two-stage, single-arm, phase 2 study of treatment with everolimus in patients with advanced (unresectable or metastatic) pancreatic neuroendocrine tumor (NET) after failure of cytotoxic chemotherapy.

Stratum 1, consisted of patients not receiving chronic Octreotide Depot therapy, will receive everolimus monotherapy at 10 mg/day.

Stratum 2, consisting of patients with tumors that have progressed during Octreotide Depot treatment will continue their entry dose of Octreotide Depot plus everolimus 10 mg/day.

Safety/Efficacy of Everolimus in Adults With Advanced Pancreatic Neuroendocrine Cancer Not Responsive to Chemotherapy

An Open Label, Stratified, Single-arm Phase II Study of Everolimus in Patients With Advanced Pancreatic Neuroendocrine Tumor (NET) After Failure of Cytotoxic Chemotherapy

Objective response rate was defined by RECIST criteria: Partial response (PR) must have ≥ 30% decrease in the sum of longest diameter of all target lesions, from the baseline sum. Complete response (CR) must have disappearance of all target and non-target lesions. For CR or PR, tumor measurements must be confirmed by 2nd assessments within 4 weeks. Progression = 20% increase in the sum of longest diameter of all target lesions, from smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions.

Duration of overall response applies only to patients whose best overall response was complete response (CR) or partial response (PR):

* Complete Response (CR) = at least two determinations of CR at least 4 weeks apart before progression.
* Partial response (PR) = at least two determinations of PR or better at least 4 weeks apart before progression.

Progression = 20% increase in the sum of the longest diameter of all target lesions, from the smallest sum of longest diameter of all target lesions recorded at or after baseline; or a new lesion; or progression of non-target lesions

Adverse events are defined as any unfavorable and unintended diagnosis, symptom, sign (including an abnormal laboratory finding), syndrome or disease which either occurs during study, having been absent at baseline, or, if present at baseline, appears to worsen. Serious adverse events are any untoward medical occurrences that result in death, are life threatening, require (or prolong) hospitalization, cause persistent or significant disability/incapacity, result in congenital anomalies or birth defects, or are other conditions which in judgment of investigators represent significant hazards.

Progression free survival (PFS) is defined as the time from randomization to the date of first documented disease progression or death from any cause. The Kaplan-Meier estimate of the PFS survival function was constructed.

Median PFS was obtained and displayed along with 95% confidence intervals.

Overall survival measures the time of survival , with any response or disease progression, until death. The OS is defined as the time from date of start of treatment to date of death due to any cause.

If a patient is not known to have died, survival was censored at the date of last contact. In each treatment stratum, the Kaplan-Meier estimate of the overall survival function was constructed.

For all patients in both strata, a blood sample for everolimus trough level determination will be collected immediately prior to the everolimus administration on Cycle 1 Day 15, Cycle 2 Day 1, and every month thereafter. A treatment cycle was defined as 28 days of consecutive daily treatment with everolimus and treatment continued until tumor progression. It is critical that patients not take their daily everolimus dose before the sample is drawn.

The effect of Octreotide Depot on the trough concentrations of everolimus was assessed at Cycle 1 Day 15.

Stratum 1 patients who were not receiving regular Octreotide Depot therapy. These patients were to receive everolimus monotherapy at 10 mg/day. Patients were instructed to take two 5 mg tablets of everolimus orally with a glass of water, once daily (preferably in the morning). Dosing was strongly recommended to occur at the same time every day.

Stratum 1: Everolimus 10 mg

Stratum 2 participants who had received at least three consecutive months of Octreotide Long Acting Depot therapy prior to enrollment. These patients also received Everolimus 10 mg/day in addition to continuing their entry dose of Octreotide Depot.

Stratum 2: Everolimus 10 mg + Octreotide Depot

Total

Age Continuous

Sex: Female, Male

Novartis Study Director

The full analysis set (FAS) consisted of all patients who received at least one dose of everolimus.

Objective Response Rate: Percentage of Participants With Best Over All Response of Complete Response or Partial Response by Central Radiology Review (Stratum 1) Based on Response Evaluation Criteria in Solid Tumors (RECIST)

Full Analysis Set (FAS) consisted of all patients who received at least one dose of everolimus. Only those patients whose best overall response was complete response (CR) or partial response (PR) were included in this analysis.

Duration of Overall Response (Stratum 1) Based on Response Evaluation Criteria in Solid Tumors (RECIST)- Central Radiology Review

Stratum 2 participants who had received at least three consecutive months of Octreotide Long Acting Depot therapy prior to enrollment. These patients also received Everolimus 10 mg/day in addition to continuing their entry dose of Octreotide Depot.

Patients were instructed to take two 5 mg tablets of everolimus orally with a glass of water, once daily (preferably in the morning). Dosing was strongly recommended to occur at the same time every day.

Very low number of patients demonstrated a partial response, the median duration of response as per central review has not been calculated.

Duration of Overall Response (Stratum 2) Based on Response Evaluation Criteria in Solid Tumors (RECIST)- Central Radiology Review

Full Analysis Set (FAS) was consisted of all patients who received at least one dose of everolimus.

Objective Response Rate: Percentage of Participants With Best Over All Response of Complete Response or Partial Response by Central Radiology Review (Stratum 2) Based on Response Evaluation Criteria in Solid Tumors (RECIST)

Adverse Events

Death

Serious Adverse Events

The safety population consists of all patients who received at least one dose of everolimus and had at least one post-baseline safety assessment.

Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs)[Stratum 1]

Number of Participants With Adverse Events (AEs), Death, Serious Adverse Events (SAEs) [Stratum 2]

Time to Progression Free Survival (PFS) Per Central Radiology Review (Stratum 1)

Time to Progression Free Survival (PFS) Per Central Radiology Review (Stratum 2)

The full analysis set consisted of all patients who received at least one dose of everolimus.

Time to Overall Survival (OS)(Stratum 1)

Time to Overall Survival (OS) (Stratum 2)

Full Analysis Set (FAS) is consisted of all patients who received at least one dose of everolimus. Patients with everolimus pharmacokinteic samples, with nonzero concentration, at Cycle 1 Day 15 were included

Everolimus Trough Level Determination by Pharmacokinetics Parameter in Both Strata (Stratum 1 and 2)

Cycle 1 Day 1 (pre-treatment baseline) (n=37)

Cycle 2 Day 1 (n= 38)

Full Analysis Set (FAS) is consisted of all patients who received at least one dose of everolimus. Patients with Octreotide Depot pharmacokinetic samples, with nonzero concentration, at Cycle 1 Day 1 or Cycle 2 Day 1 were included.

Effect of Octreotide Depot on the Trough Concentrations of Everolimus

Overall Study

Gallbladder Neoplasms

Biliary Tract Neoplasms

Biliary Tract Diseases

Gallbladder Diseases

Gallbladder Cancer

Gemcitabine

Oxaliplatin

Capecitabine

Everolimus 10 mg. PO/day in addition to standard of care

Standard of care alone i.e Capecitabine and Oxaliplatin or Gemcitabine and oxaliplatin

Oral Everolimus 10 mg daily in addition to standard of care i.e. GemOx or CapOx

Standard of care

Manoj Pandey

Madhumita Tripathi

Gallbladder cancer (GBC) is the most common malignant tumour of the biliary tract. It is also the most aggressive cancer of the biliary tract with the shortest median survival from the time of diagnosis. Currently, radical resection is the most effective strategy to potentially cure GBC. Chemotherapy and radiotherapy have been employed as adjuvant and palliative setting, however, the overall survival is still dismal. This study aim to evaluate the addition of Everolimus in addition to standard of care in gallbladder cancer.

Gallbladder cancer is the most common malignant tumour of the biliary tract. It is also the most aggressive cancer of the biliary tract with the shortest median survival from the time of diagnosis. While the incidence rate of GBC varies widely, it has a unique distribution pattern in some regions, where Chile, India, some other Asian countries, Eastern European, and Latin American countries have reported more cases than the rest of the world every year. The other factors, which associated with chronic inflammation and disease pathogenesis, such as hepatobiliary stones, liver flukes, and Salmonella frequently observed in these areas, also constitute the other high-risk factors of bile tract cancer (BTC) including GBC.

Currently, radical resection is the most effective strategy to potentially cure GBC. The non-surgical therapies engaged in patients were primarily composed of chemotherapy and radiotherapy. additional therapeutic strategies including next-generation sequencing (NGS), whole-exome sequencing (WES), RNA-sequencing (RNAseq), and single-cell isolation, as well as characterization that have fundamentally opened a novel view enabled to globally identify genetic and epigenetic features and key molecules as potential therapeutic target.

Advanced or unrespectable locally advanced disease has a poor prognosis with limited systemic treatment options. Combination platinum-gemcitabine chemotherapy is an active first-line treatment regimen.in particular, specific target treatment, immune therapy, vaccine therapy, biotherapy and nanoparticles have been intensively developed in preclinical and clinical trials.

One of target treatment is Mammalian target of rapamycin (mTOR) inhibitors, as The mTOR signaling pathway has critical roles in mammalian metabolism and physiology. The de-regulated activity of mTOR is involved in many pathophysiological conditions, such as aging, Alzheimer's disease, diabetes, obesity, and cancer.

Everolimus is a derivative of rapamycin that selectively inhibits mTORC1 (mammalian target of rapamycin complex 1), a key protein kinase complex which regulates cell growth, proliferation and survival. Activation of mTORC1 is mediated by the phosphatidylinositol 3-kinase (PI3K) pathway through activation of AKT/ PKB and subsequent inhibition of the tuberous sclerosis complex.

Addition of Everolimus to Standard of Care in Carcinoma Gallbladder

A Randomized Controlled, Open Labeled, Two Arm, Study of Addition of Everolimus to Standard of Care in Carcinoma Gallbladder

Progression free survival from diagnosis to disease progression or death

Survival time from the enrollment till the study closure

Toxicity of addition of Everolimus to standard of care as measured by WHO toxicity criteria

Banaras Hindu University

Professor

Intestinal Neoplasms

Stomach Neoplasms

Intestinal Diseases

Stomach Diseases

Gastro-enteropancreatic Neuroendocrine Tumor

Stomach Cancer

Somatostatin

Sunitinib

Lanreotide

Angiogenesis Inhibitors

Growth Inhibitors

Part 1 is an uncontrolled dose de-escalation study to confirm the safety and determine the RP3D of RYZ101 based on Bayesian optimal interval design. Eligible participants will be enrolled in cohorts of 6 to receive RYZ101 up to 4 infusions every 8 weeks. If the initial dose level is not tolerated, the dose will be de-escalated; up to 3 dose levels will be assessed.

Actinium 225 radiolabeled somatostatin analog (SSA) for injection

Investigator's choice of standard of care between everolimus, sunitinib, octreotide, or lanreotide.

RYZ101

Sunitinib 37.5 MG

High-dose octreotide LAR 60 mg Q4W by i.m. injection

Octreotide LAR 60 MG Injection

High dose frequency lanreotide 120 mg Q2W by deep s.c. injection

Lanreotide 120Mg Sa Susp Inj Syringe

Denis Ferreira, MD

This study aims to determine the safety, pharmacokinetics (PK) and recommended Phase 3 dose (RP3D) of RYZ101 in Part 1, and the safety, efficacy, and PK of RYZ101 compared with investigator-selected standard of care (SoC) therapy in Part 2 in subjects with inoperable, advanced, well-differentiated, somatostatin receptor expressing (SSTR+) gastroenteropancreatic neuroendocrine tumors (GEP-NETs) that have progressed following treatment with Lutetium 177-labelled somatostatin analogue (177Lu-SSA) therapy, such as 177Lu-DOTATATE or 177Lu-DOTATOC (177Lu-DOTATATE/TOC), or 177Lu-high affinity \[HA\]-DOTATATE.

Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy

Phase 1b/3 Global, Randomized, Controlled, Open-label Trial Comparing Treatment With RYZ101 to Standard of Care Therapy in Subjects With Inoperable, Advanced, SSTR+, Well-differentiated GEP-NETs That Have Progressed Following Prior 177Lu-SSA Therapy

Incidence and severity of AEs by NCI CTCAE v5, including SAEs, laboratory changes, ECG changes, and other safety findings

Relationship between biomarkers, including but not limited to CgA in the serum and (5-HIAA) in the urine, with AEs of special interest and/or efficacy endpoints (e.g., PFS, OS, BOR, DoR)

Measured by continuous ECG recording using a 12-lead Holter monitoring device

Incidence of DLTs during the first 56 days of study treatment will be assessed.

PFS will be defined as the time from the date of randomization until the date of progression (as determined by BICR from tumor assessments using RECIST v1.1) or death due to any cause, whichever occurs earlier.

Calculated mean TIAC (hours) and absorbed radiation dose coefficients (mGy/MBq) to critical organs (e.g., the kidneys and bone marrow) and tumors after the 1st and 4th RYZ101 infusions will be assessed

OS will be defined as the time from the date of randomization until the date of death due to any cause.

ORR, as determined by BICR according to RECIST v1.1.

ORR, as assessed by the Investigator according to RECIST v1.1

Assessed by BICR and by the Investigator according to RECIST v1.1

Only for subjects with a RECIST v.1.1 response, assessed by BICR and by the Investigator according to RECIST v1.1

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Safety/Efficacy of Everolimus in Adults With Advanced Pancreatic Neuroendocrine Cancer Not Responsive to Chemotherapy	NCT00363051	Islet Cell Carc... Neuroendocrine ... Neuroendocrine ... Pancreatic Neop...	Everolimus 10 m... Octreotide Depo...	18 Years -	Novartis
Addition of Everolimus to Standard of Care in Carcinoma Gallbladder	NCT05833815	Gallbladder Can...	Everolimus 10 m... Standard of car...	18 Years - 99 Years	Banaras Hindu University
Study of RYZ101 Compared With SOC in Pts w Inoperable SSTR+ Well-differentiated GEP-NET That Has Progressed Following 177Lu-SSA Therapy	NCT05477576	GEP-NET Gastroenteropan... Gastroenteropan... Neuroendocrine ... Carcinoid Carcinoid Tumor Pancreatic NET	RYZ101 Everolimus 10 m... Sunitinib 37.5 ... Octreotide LAR ... Lanreotide 120M...	18 Years -	RayzeBio, Inc.
Addition of Everolimus to Standard of Care in Carcinoma Gallbladder	NCT05833815	Gallbladder Can...	Everolimus 10 m... Standard of car...	18 Years - 99 Years	Banaras Hindu University

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