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Sirolimus

Temsirolimus

MTOR Inhibitors

AZD2014 dose escalation phase in Part A and expansion phase in Part B.

Dose escalation phase: a single dose taken orally (solution or tablet) of AZD2014 on single dose day 1 (visit 2), followed by once or twice daily continuous dosing after a washout period (48 hours - 7 days) at visit 4, until discontinuation or withdrawal or Single or multiple doses taken orally (solution or tablet) of AZD2014 taken intermittently until discontinuation or withdrawal. Expansion phase: twice daily dosing from day 1 until discontinuation or withdrawal or a single dose taken orally of AZD2014 on single dose day 1 (visit 2), followed by a single dose on second single dose day 1 (visit 3) after a washout period (48 hours - 7 days) followed by once or twice daily continuous dosing after a washout period (48 hours - 7 days) at visit 4, until discontinuation or withdrawal or single or multiple doses taken orally (solution or tablet) of AZD2014 taken intermittently until discontinuation or withdrawal.

AZD2014

Dr. Udai Banerji

Elisabeth Oelmann

The main purpose of the study is to establish a safe dose of the drug by providing information on any potential side effects this drug may cause and collecting data about how a patient's cancer responds to the drug. The study will also assess the blood levels and action of AZD2014 in the body over a period of time and will indicate whether the drug has an effect on the types of cancer the patients have.

Study to Assess the Safety, Tolerability, Pharmacokinetics (PK) and Preliminary Efficacy of AZD2014

A Phase I, Open Label, Multicentre Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the mTor Kinase Inhibitor AZD2014 Administered Orally to Patients With Advanced Solid Malignancies

Maximum Tolerated Dose (MTD) was determined by testing various doses and schedules of AZD2014 in cohorts of 3-6 evaluable patients. MTD reflects the highest dose of drug at each schedule that did not cause a DLT in \>1 patient

Best Objective Response per Response Evaluation Criteria in Solid Tumours Criteria (RECIST) 1.1 for target and non target lesions assessed by CT, MRI or X-ray; Complete Response (CR), Disappearance of all target lesions since baseline; Partial Response (PR), At least a 30 percent decrease in the sum of diameters of target lesions; Progressive Disease (PD), At least a 20 percent increase in the sum of diameters of target lesions and an absolute increase of at least 5mm

Maximum concentration following single dose (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered)

Area under the curve following single dose Continuous dosing - AUC parameter used Intermittent dosing - AUC(0-12) used (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered)

Cmax at steady state (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered)

AUC at steady state Continuous dosing - AUCss used Intermittent dosing - Weekly AUC used (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered)

Fraction dose excreted unchanged in the urine from 0-12 hours after a single dose (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered)

Fraction dose excreted unchanged in the urine from 0-12 hours after dosing (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered)

Renal Clearance (n varies between PK outcome measures as a subset of the PK analysis set was used with reportable AZD2014 plasma concentrations and PK parameters at that visit who have no important adverse events or protocol deviations that may impact PK at that visit, which means that different amounts of data were available for different parameters depending on what visits the parameter covered)

Phosphorylation levels of 4EBP1 from peripheral blood mononuclear cell (Patients with undetectable values at baseline have been excluded)

Phosphorylation levels of AKT from PRP (Patients with undetectable values at baseline have been excluded)

Partial metabolic responses measured by 2-\[F-18\]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) (or FDG-PET/Computed Tomography (CT)) with a comparison to baseline (pre-dose)

Complete metabolic responses measured by 2-\[F-18\]-fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) (or FDG-PET/Computed Tomography (CT)) with a comparison to baseline (pre-dose)

AstraZeneca

Continuous BD solution dosing cohorts 25mg, 50mg, 70mg, 100mg Continuous BD tablet dosing cohort Fed/Fasted 50mg Continuous QD solution dosing cohorts 75mg, 125mg Continuous Qd tablet dosing cohorts 100mg, 125mg, 175mg Intermmittent BD tablet dosing cohorts 100mg, 125mg, 170mg, 225mg

Part A - AZD2014 100 mg BD Solution

Part A - AZD2014 100 mg QD Tablet

Part A - AZD2014 125 mg QD Solution

Part A - AZD2014 125 mg QD Tablet

Part A - AZD2014 175 mg QD Tablet

Part A - AZD2014 25 mg BD Solution

Part A - AZD2014 50 mg BD Solution

Part A - AZD2014 70 mg BD Solution

Part A - AZD2014 75 mg QD Solution

Part A - Intermittent AZD2014 100 mg BD Tablet

Part A - Intermittent AZD2014 125 mg BD Tablet

Part A - Intermittent AZD2014 170 mg BD Tablet

Part A - Intermittent AZD2014 225 mg BD Tablet

Part B - AZD2014 50 mg BD Solution

Part B - AZD2014 50 mg BD Tablet Fasted/Fed

Part B - AZD2014 BD 50 mg Tablet Fed/Fasted

Part B - Intermittent AZD2014 125 mg BD Tablet

Part B - Intermittent AZD2014 170 mg BD Tablet

Part A 25mg BD Soln Cont

Part A 50mg BD Soln Cont

Part B 50mg BD Soln Cont

Part B Fed/Fasted 50mg BD Tab Cont

Part A 75mg QD Soln Cont

Part A 125mg QD Soln Cont

Part A 100mg QD Tab Cont

Part A 125mg QD Tab Cont

Part A 175mg QD Tab Cont

Part A 100mg BD Tab Int

Part A 125mg BD Tab Int

Part A 170mg BD Tab Int

Part A 225mg BD Tab Int

Part B 125mg BD Tab Int

Part B 170mg BD Tab Int

Part A 70mg BD Soln Cont

Part A 100mg BD Soln Cont

Total

Age, Continuous

Sex: Female, Male

Safety Analysis Set - All patients that received at least 1 dose of AZD2014. This includes dosed patients who are not evaluable for dose escalation decision purposes.

Bryony Harrop

Number of Participants With Dose Limiting Toxicities (DLTs)

Responders

Non-responders

Stable disease ≥8 wks (a subset of non-responders)

Efficacy analysis set - Patients who received at least 1 dose of AZD2014 and have a baseline tumour assessment

Best Objective Response

Part B 50mg BD Tablet Fasted

Part B 50mg BD Tablet Fed

Maximum Concentration (Cmax) Single Dose

Area Under the Curve (AUC) Single Dose

Maximum Concentration (Cmax) at Steady State

Area Under the Curve (AUC) at Steady State

PK analysis set - A subset of Safety Analysis set who have reportable plasma concentrations and PK parameter data and who have no important protocol deviations/AEs that may impact PK

Urine PK - Fraction Dose Excreted (fe(0-12)) Single Dose

Urine PK - Fraction Dose Excreted (fe(0-12)) at Steady State

Urine PK - Renal Clearance (Renal CL) Single Dose

Urine PK - Renal Clearance (Renal CL) at Steady State

Percent Change From Baseline in p4EBP1 at 2 Hours Post Dose

Percent Change From Baseline in pAKT (S473) in Platelet Rich Plasma (PRP) at 2 Hours Post Dose

Partial Metabolic Response (PMR), Cycle 1

Partial Metabolic Response (PMR), Cycle 2

Complete Metabolic Response (CMR), Cycle 1

Complete Metabolic Response (CMR), Cycle 2

Overall Study

Neoplasms

Blood and Lymph Conditions

All Conditions

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Immune System Diseases

Symptoms and General Pathology

Heart and Blood Diseases

Skin and Connective Tissue Diseases

Rare Diseases

Leukemia

Carcinoma

Prostatic Neoplasms

Glioblastoma

Lymphoma, Large B-Cell, Diffuse

Carcinoma, Squamous Cell

Squamous Cell Carcinoma of Head and Neck

Leukemia, Lymphoid

Osteosarcoma

Neoplasm Metastasis

Lymphoma

Multiple Myeloma

Neoplasms, Plasma Cell

Hematologic Neoplasms

Leukemia, Lymphocytic, Chronic, B-Cell

Lymphoma, B-Cell

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Hematologic Diseases

Genital Neoplasms, Male

Urogenital Neoplasms

Genital Diseases

Genital Diseases, Male

Urogenital Diseases

Prostatic Diseases

Male Urogenital Diseases

Neoplastic Processes

Astrocytoma

Glioma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms, Nerve Tissue

Lymphoproliferative Disorders

Lymphatic Diseases

Immunoproliferative Disorders

Leukemia, B-Cell

Chronic Disease

Disease Attributes

Neoplasms, Bone Tissue

Neoplasms, Connective Tissue

Neoplasms, Connective and Soft Tissue

Sarcoma

Head and Neck Neoplasms

B-cell Lymphoma

Diffuse Large B-Cell Lymphoma

Chronic Graft Versus Host Disease

Lymphosarcoma

Chronic Lymphocytic Leukemia

Neuroepithelioma

Soft Tissue Sarcoma

Hormones

Part A (actively recruiting): Dose level starts with 0.5mg daily by mouth in cycles of 28 days. Level increases for different patient cohorts in 100% or 50% increments until optimal dose schedule is established for further study. Treatment continues for as long as patient benefits (i.e., until disease progression or unacceptable toxicity).

Part B: Optimal dose schedule is administered in 28-day cycles until disease progression.

CC-115

Bristol-Myers Squibb

The main purpose of this first human study with CC-115 is to assess the safety and action of a new class of experimental drug (dual DNA-PK and TOR kinase inhibitors) in patients with advanced tumors unresponsive to standard therapies and to determine the appropriate dose and tumor types for later-stage clinical trials. The bioavailability of tablet and capsule formulations under fasting and fed conditions will also be evaluated in some patients.

Latest amendment clarifies that Chronic Lymophocytic Leukemia (CLL) includes T-cell Prolymphocytic Leukemia (T-PLL). Prior treatment with some drugs targeting mTOR, P13K and related pathways is now permitted.

Study to Assess Safety and Tolerability of Oral CC-115 for Patients With Advanced Solid Tumors, and Hematologic Malignancies.

A Phase 1a/1b, Multicenter, Open Label, Dosefinding Study to Assess the Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of the Dual Dna-pk and Tor Kinase Inhibitor, Cc-115, Administered Orally to Subjects With Advanced Solid Tumors and Hematologic Malignancies

Phosphorylation inhibition determined by changes in the levels of multiple biomarkers including S6 and, 4EBP (for mTORC1), AKT (for mTORC2) and other appropriate biomarkers in circulating granulocytes and tumor tissue (when available).

Tumor response rates using appropriate objective criteria for various malignancies

Celgene

Tablets, orally administered, twice daily

AZD8055

Ian Smith

Tomohide Tamura

The primary objective is to assess the safety and tolerability of AZD8055 in Japanese patients with advanced solid tumours.

Study to Assess the Safety and Tolerability of the Tor Kinase Inhibitor AZD8055

A Phase I, Open Label, Single-centre Study to Assess the Safety and Tolerability of the Tor Kinase Inhibitor AZD8055 Administered Orally to Japanese Patients With Advanced Solid Tumours

Adenocarcinoma

Endometrial Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Uterine Diseases

Genital Diseases, Female

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Anastrozole

Aromatase Inhibitors

Antineoplastic Agents, Hormonal

Enzyme Inhibitors

Estrogens

Estrogen Antagonists

Estrogen Receptor Antagonists

Hormone Antagonists

Following inclusion, patients will be randomized (2:1) to receive Arm A : AZD2014 + anastrozole Arm B : anastrozole alone

Mode of Action Selective and specific mTOR kinase inhibitor targeting both mTORC1 and mTORC2 complexes.

Route of Administration Oral

Dosage regimen 125mg BID with intermittent schedule (2 days of treatment followed by 5 days off (500mg/week))

Duration of treatment Until the patient experiences unacceptable toxicity, disease progression and/or treatment is discontinued per patient or investigator request.

Therapeutic Class Aromatase inhibitor

Mode of Action Potent and highly selective non-steroidal aromatase inhibitor.

Route of Administration Oral

Dosage regimen

1 mg tablet once a day

Duration of treatment Patients may continue treatment with anastrozole until the patient experiences unacceptable toxicity, disease progression and/or treatment is discontinued per patient or investigator request.

Pierre-Etienne HEUDEL, MD

The investigators hypothesize that the dual inhibition of mTORC1/mTORC2 by AZD2014 combined with inhibition of aromatase enzyme by anastrozole will act synergistically and may be an interesting therapeutic option for endometrial cancer with a manageable toxicity profile.

The investigators proposal is to conduct a multicenter, 2-step, randomized, Phase I/II trial to evaluate the safety and efficacy of a combination treatment associating anastrozole to AZD2014 in advanced endometrial cancer patients.

The study is divided in 2 steps :

* A safety run-in phase aiming to evaluate the safety of the proposed combination AZD2014 + anastrozole (Arm A) versus anastrozole alone (Arm B). No dose escalation is scheduled (doses are based on maximum tolerated dose (MTD) defined for AZD2014 and the summary of product characteristics (SPC) of anastrozole). However, dose de-escalation for AZD2014 will be applied in case of toxicity.
* A two-stage randomized Phase II part aiming to evaluate the clinical benefit of the AZD2014 + anastrozole (Arm A) combination therapy versus anastrozole (Arm B).

TREATMENT PLAN :

Following randomisation patients will receive Arm A : AZD2014 plus anastrozole or Arm B: anastrozole alone AZD2014 will be administered with an intermittent schedule i.e. 125 mg bis in die (BID) intermittent with 2 days on followed by 5 days off per week for a total weekly dose of 500 mg/week (250mg D1 and D2, 5 days off) Anastrozole will be administered at the standard dose defined in the SPC i.e. 1mg/d, per os, continuously.

Both treatment will be administered until progressive disease (PD), unacceptable toxicity or willingness to stop.

STATISTICS :

A total of 72 patients will be randomized in the study.

Safety run-in Phase on the first 9 patients randomized - As no dose escalation will be performed, the safety will be evaluated following the treatment and 8-week follow-up of the first 6 patients by the experimental association AZD2014+anastrozole (experimental arm). By similarity to a classic 3+3 design, based on binomial probabilities, there is a 90% probability of observing one or more patients with a toxicity event, if that event occurs in at least 32% of the target population. Assuming a 2:1 randomization ratio, a total of 9 patients (Arm A - Experimental: 6 patients, Arm B - Control: 3 patients) will be enrolled in this safety run-in phase and will be included in the evaluation of Phase II part.

Phase II The sample size calculation was based on a Simon optimal two-stage design, with a minimum success (8-week non progression) rate considered of interest p1=60% and an uninteresting rate p0=40%. Assuming a type I error alpha of 0.05 and 80% power, 46 evaluable patients are needed in the experimental arm to reject the null hypothesis H0: p≤p0 versus the alternative hypothesis H1: p ≥ p1 in a unilateral situation (16 patients in Stage I and 30 additional patients in Stage II).

With a 2:1 randomization and based on the assumption that 5% of the patients may be non-evaluable, a total of 72 patients will be included in the study : 48 patients in Arm A - experimental and 24 patients in Arm B - control).

DATA ENTRY, DATA MANAGEMENT AND STUDY MONITORING All the data concerning the patients will be recorded in the electronic case report form (eCRF) throughout the study. serious adverse event (SAE) reporting will be also paper-based by e-mail and/or Fax.

The sponsor will perform the study monitoring and will help the investigators to conduct the study in compliance with the clinical trial protocol, Good Clinical Practices (GCP) and local law requirements.

Hormone Receptor Positive endometrIal Carcinoma Treated by Dual mTORC1/mTORC2 Inhibitor and Anastrozole (VICTORIA)

A Multicentric, Randomized, Non Comparative, Open-label Phase I/II Evaluating AZD2014 (Dual Mammalian Target of Rapamycin Complex 1/2 (mTORC1/mTORC2) Inhibitor) in Combination With Anastrozole Versus Anastrozole Alone in the Treatment of Metastatic Hormone Receptor-positive Endometrial Adenocarcinoma

Severe toxicities defined as

* Any grade ≥ 4 treatment related toxicity
* Any grade≥ 3 treatment related toxicity lasting more than 7 days

Centre Leon Berard

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Study to Assess the Safety, Tolerability, Pharmacokinetics (PK) and Preliminary Efficacy of AZD2014	NCT01026402	Advanced Solid ...	AZD2014	18 Years - 150 Years	AstraZeneca
Study to Assess Safety and Tolerability of Oral CC-115 for Patients With Advanced Solid Tumors, and Hematologic Malignancies.	NCT01353625	Glioblastoma Mu... Squamous Cell C... Prostate Cancer Ewing's Osteosa... Chronic Lymphoc... Neoplasm Metast...	CC-115	18 Years -	Celgene
Study to Assess the Safety and Tolerability of the Tor Kinase Inhibitor AZD8055	NCT00973076	Cancer Solid Tumors Advanced Solid ...	AZD8055	20 Years -	AstraZeneca
Hormone Receptor Positive endometrIal Carcinoma Treated by Dual mTORC1/mTORC2 Inhibitor and Anastrozole (VICTORIA)	NCT02730923	Endometrial Car... Metastatic Carc... Hormone Recepto...	AZD2014 Anastrozole	18 Years -	Centre Leon Berard
Study to Assess Safety and Tolerability of Oral CC-115 for Patients With Advanced Solid Tumors, and Hematologic Malignancies.	NCT01353625	Glioblastoma Mu... Squamous Cell C... Prostate Cancer Ewing's Osteosa... Chronic Lymphoc... Neoplasm Metast...	CC-115	18 Years -	Celgene

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