All Drugs and Chemicals

Protein Kinase Inhibitors

Days 1, 3, 5 of a weekly schedule in dose escalation cohorts of three patients. Continuous dosing until progression or unacceptable toxicity develops up to a maximum of 12 cycles.

AT13148

The purpose of this first clinical study of the noval multiple AGC kinase inhibitor, AT13148, is to identify the recommended dose for future studies in cancer patients by exploring the safety and maximum tolerated dose and biological effects in patients with advanced solid tumours.

AT13148 is a new drug which looks promising in laboratory studies. We now wish to find out if it will be useful in treating patients with cancer. AT13148 is a type of drug called a protein kinase inhibitor. It blocks several different chemical messengers (enzymes) called AGC kinase proteins. These chemical messengers are part of the signaling process within cells which can make cells produce chemicals that trigger and control cell growth and cell death. In some types of cancer these chemical messengers are 'switched on' or 'switched off' permanently due to changes in the genes of cells called "gene mutations" leading to uncontrolled cancer cell growth. AT13148 targets multiple protein kinases from three families of kinases unlike many of the other protein kinase inhibitors currently being tested which target just one or two kinases. This may mean that it will work better and in a wider group of cancer patients. Patients will not be selected to take part based on having these gene mutations for this first trial because we want to learn more about which mutations are most important but this would be the hope for future trials. The patient population anticipated to benefit from this drug includes certain types of breast, prostate and ovarian cancer which more commonly have these gene mutations.

Phase I Study of AT13148, a Novel AGC Kinase Inhibitor

A Cancer Research UK Phase I First in Man Study of the Novel AGC Kinase Inhibitor AT13148 Given Orally in Patients With Advanced Solid Tumours.

Cancer Research UK

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Skin and Connective Tissue Diseases

Immune System Diseases

Prostatic Neoplasms

Breast Neoplasms

Hypersensitivity

Anti-Infective Agents

Itraconazole

Hydroxyitraconazole

Clotrimazole

Miconazole

Antifungal Agents

Enzyme Inhibitors

Cytochrome P-450 Enzyme Inhibitors

Hormones

Hormone Antagonists

Cytochrome P-450 CYP3A Inhibitors

Subjects will receive a single oral dose of capivasertib on Day 1 during treatment period 1, itraconazole on Days 3, 4, and 5 during treatment period 2, and single oral dose of capivasertib plus a dose of itraconazole on Day 6, followed by itraconazole alone on Day 7 during treatment period 3.

Subects will be administered single doses of capiversatib on Day 1 and Day 6.

Capivasertib

Subjects will be administered itraconazole twice daily on Day 3, followed by once daily doses in the morning for 4 days.

Rainard Fuhr, Dr.

This study will be an open-label, fixed sequence study in healthy subjects (vasectomized males and females of non-childbearing potential), performed at a single study centre.

The study will comprise:

* A screening period of maximum 21 days;
* A fixed sequence of 3 treatment periods: Treatment Period 1: Capivasertib only, Treatment Period 2: Itraconazole pre-treatment (run-in) period, and Treatment Period 3: Capivasertib and itraconazole in combination.
* A Follow-up Visit at 7 to 14 days after the last capivasertib PK sample in Treatment Period 3.

There will be no washout between Treatment Period 2 and Treatment Period 3. Each subject will be involved in the study for up to 7 weeks.

A Study to Assess How Itraconazole Affects the Uptake and Elimination of Capivasertib in the Body

An Open-label, Fixed Sequence Study in Healthy Subjects to Assess the Pharmacokinetics of Capivasertib When Administered Alone and In Combination With Itraconazole

Assessment of AUClast of capivasertib and its major metabolite (AZ14102143).

Assessment of tmax of capivasertib and its major metabolite (AZ14102143).

Assessment of t½λz of capivasertib and its major metabolite (AZ14102143).

Assessment of λz of capivasertib and its major metabolite (AZ14102143).

Assessment of AUCinf of major metabolite (AZ14102143) of capivasertib.

Assessment of Cmax of major metabolite (AZ14102143) of capivasertib.

Assessment of safety and tolerability of capivasertib alone and in combination with itraconazole.

Parexel

AstraZeneca

Nervous System Diseases

Rare Diseases

Pinealoma

Neoplasms, Neuroepithelial

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Glandular and Epithelial

Neoplasms, Nerve Tissue

Brain Neoplasms

Central Nervous System Neoplasms

Nervous System Neoplasms

Brain Diseases

Central Nervous System Diseases

Pineoblastoma

Pineocytoma

Neuroepithelioma

Antineoplastic Agents

Central Nervous System Depressants

Micronutrients

Pharmaceutical Solutions

Gastrointestinal Agents

Dermatologic Agents

Vitamins

Herbal and Botanical

Amino Acids

Irinotecan

Ethanol

Ascorbic Acid

Temozolomide

Carboxymethylcellulose Sodium

Sirolimus

Dasatinib

Sorbitol

Immunosuppressive Agents

Titanium dioxide

Temsirolimus

MTOR Inhibitors

Topoisomerase I Inhibitors

Alkylating Agents

Antineoplastic Agents, Alkylating

Anti-Bacterial Agents

Antibiotics, Antitubercular

Immunologic Factors

Tyrosine Kinase Inhibitors

Vitamin C

Soy Bean

Tyrosine

Pharmacotherapeutic Group: Antineoplastic agents - Other alkylating agents, ATC-Code: L01A X03 Excipients: Capsule content: Anhydrous lactose, Sodium starch glycolate Type A, Colloida anhydrous silica, Tartaric acid, Stearic acid. Capsule shell: Gelatine, Titanium dioxide (E171).

Printing ink: Shellac Propylene glycol, Titanium dioxide (E171), Sunset yellow FCF Aluminium Lake (E110) Formulation: capsule, hard Route of Administration: orally; Temomedac hard capsules should be administered in the fasting state. The capsules must be swallowed whole with a glass of water and must not be opened or chewed

Pharmacotherapeutic Group: cytostatic topoisomerase-I-inhibitor ATC-Code: L01XX19 Excipients: Sorbitol (E420), lactic acid, sodium hydroxid (to adjust the pH to 3.5), water for injection Formulation: concentrate for solution for infusion Route of Administration: intravenously

Pharmacotherapeutic Group: protein kinase inhibitor ATC-Code: L01XE06 Excipients: Tablet core: Lactose monohydrate, Cellulose, microcrystalline, Croscarmellose sodium, Hydroxypropyl cellulose, Magnesium stearate. Film-coating: Hypromellose, Titanium dioxide, Macrogol 400 Formulation: film coated tablet Route of Administration: orally. Patients should be instructed to swallow the tablets as a whole and not to split, chew, or crush them.

Pharmacotherapeutic Group: Immunosuppressive agents - mTOR Inhibitors ATC-Code: L04A A10 Excipients: Polysorbat 80, Phosal 50 PG ((3-sn-Phosphatidyl)cholin from Soy beans, Propylenglycol, lipid acid mono- and -diglyzeride from Soy oil, Ethanol (1,5% bis 2,5%), Soy liid acid and Palmitoyl ascorbic acid) Formulation: Oral solution Route of Administration:orally

Rapamycin

Children, adolescents and young adults with relapsed or treatment refractory pineoblastoma (rPB) represent a group of patients with dismal prognosis for whom a recommended standard salvage therapy is currently not available.

The multimodal metronomic approach combining molecular targeted drugs (rapamycin and dasatinib) with conventional chemotherapy (irinotecan and temozolomide) will be investigated in a randomized fashion as new treatment strategy for patients with rPB. The intention is to assess the therapeutic benefit of molecular targeted drugs for the treatment of rPB.

The combination of irinotecan and temozolomide showed activity in the treatment of several solid organ tumors, brain tumors and neuroblastoma. In one study relapsed neuroblastoma (rNB) patients received a median of 5 courses of 5 days irinotecan and temozolomide every 3 to 4 weeks with a cumulative dose of 35% lower than in the RIST design. 33% had disease regression with 8% CR or PR. A phase II study in rNB also using irinotecan and temozolomide with a substantially lower intensity showed a response rate of 15%.

The combination of a mTOR inhibitor with a multi-kinase inhibitor demonstrated in preclinical studies a synergistic effect on cell cycle arrest, apoptosis and sensitization for radio- and chemotherapy. It is assumed that this combination of molecular targeted drugs with a tolerable conventional chemotherapy consisting of irinotecan and temozolomide can substantially improve the outcome of this patient population. A group of 20 rNB patients treated with the RIST therapy approach in a compassionate use setting showed an overall survival of 55% at a median of 80 weeks with a tolerable adverse event profile.

Prospective Pilot Trial to Assess a Multimodal Molecular Targeted Therapy in Children, Adolescent and Young Adults With Relapsed or Refractory High-grade Pineoblastoma

According to:

* Imaging criteria to

  * MRI, CT or
  * CSF evaluations or
* date of death of any cause

According to:

• Imaging criteria to

* MRI, CT or
* CSF evaluations

According to:

Lansky and Karnofsky Scores

Assessment according to the latest version of the CTC criteria. In particular due to the expected AE Profile:

Myelosuppressive measures (RBC, PLT units) Infectious complications Gastrointestinal problems

University of Regensburg

Professor Dr. med.

Blood and Lymph Conditions

Symptoms and General Pathology

Leukemia

Leukemia, Myeloid

Leukemia, Myelogenous, Chronic, BCR-ABL Positive

Myeloproliferative Disorders

Bone Marrow Diseases

Hematologic Diseases

Neoplastic Processes

Chronic Disease

Disease Attributes

Myeloid Leukemia

Chronic Graft Versus Host Disease

Chronic Myeloid Leukemia

Chronic Myeloproliferative Disorders

Nilotinib

Imatinib Mesylate

Diagnosis within 6 months of date of first cytogenetic analysis confirming Philadelphia chromosome with (9;22) translocation by standard conventional cytogenetic analysis.

Resistant or Intolerant to either imatinib or dasatinib

Resistant or intolerant to either imatinib or dasatinib - at the end no patients were enrolled in this arm.

Nilotinib supplied in 50mg, 150mg, and 200mg capsules. It was administered orally at 230mg/m2, twice daily for up to 66 cycles (1 cycle = 28 days). Dose administration was rounded to the nearest 50mg dose (to a maximum dose of 400mg).

nilotinib

Novartis Pharmaceuticals

To evaluate the safety, efficacy and pharmacokinetics of nilotinib over time in the Ph+ chronic myelogenous leukemia (CML) in pediatric patients (from 1 to \<18 years).

The study was designed as a multi-center, open-label, non-controlled phase II study to assess efficacy, safety and PK parameters of 230 mg/m2 twice daily nilotinib in pediatric patients (1 to \<18 years old). The study population consisted of three cohorts of Ph+ CML pediatric patients:

* Cohort 1: Ph+ CML-CP patients resistant or intolerant to either imatinib or dasatinib
* Cohort 2: Ph+ CML-AP patients resistant or intolerant to either imatinib or dasatinib
* Cohort 3: Newly-diagnosed Ph+ CML-CP patients in first chronic phase A minimum number of 50 pediatric patients (from 1 to \<18 years) were enrolled in the study. Of them, at least 15 patients were Ph+ CML-CP patients resistant or intolerant to either imatinib or dasatinib, and at least 15 were newly-diagnosed Ph+ CML-CP patients in first chronic phase patients. There was no minimum number of patients required for Ph+ CML-AP patients resistant or intolerant to either imatinib or dasatinib.

Based on enrollment forecasts as of Jan 2015, and to reflect the agreements with the US FDA and the PDCO, the study remained open for enrollment until the targeted number of 50 patients with at least 15 newly diagnosed Ph+CML patients was achieved or until 31May2015, whichever was later.

Patients who completed the study were treated with nilotinib for a total of 66 cycles of 28 days unless the patient prematurely discontinued study treatment.

The primary analysis cut-off date was the date when all patients enrolled in the trial either completed their visit for treatment cycle 12 or had discontinued study treatment early (EoT/early discontinuation visit). These analyses were reported in the 12-cycle clinical study report (CSR). A 24-cycle analysis was done when all patients had either completed their 24-cycle treatment visit or had discontinued study treatment early.

At trial end, a final comprehensive CSR of all data collected during the trial was produced.

Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients.

A Multi-center, Open Label, Non-controlled Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Pediatric Patients With Newly Diagnosed Ph+ Chronic Myelogenous Leukemia (CML) in Chronic Phase (CP) or With Ph+ CML in CP or Accelerated Phase (AP) Resistant or Intolerant to Either Imatinib or Dasatinib

Novartis is committed to sharing with qualified external researchers, access to patient-level data and supporting clinical documents from eligible studies. These requests are reviewed and approved by an independent review panel on the basis of scientific merit. All data provided is anonymized to respect the privacy of patients who have participated in the trial in line with applicable laws and regulations.

This trial data availability is according to the criteria and process described on www.clinicalstudydatarequest.com

The summary of bone age and Dual-energy X-ray absorptiometry (DEXA) by cohort. Alteration of bone biochemical markers of hand and wrist X-Ray evaluation was observed in bone age standard deviation scores (SDS) and for bone mineral density for DEXA before and after treatment with nilotinib.

MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. A patient was counted as having MMR at 6 cycles if the patient met the MMR criteria at the Cycle 6 Visit.

MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. A patient was counted as having MMR by 12 cycles if the patient met the MMR criteria at least once at any time between first study drug intake and Cycle 12 visit included.

Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as CCyR at 12 cycles if the patient met the CCyR criteria at the Cycle 12 Visit.

Major molecular response (MMR) was defined as BCR-ABL/ABL % ≤ 0.1% by IS as measured by RQ-PCR, confirmed by duplicate analysis of the same sample.

MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR (Real time quantitative polymerase chain reaction). BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL ratio by percentage: \> 0.0032 to ≤ 0.01% is equal to a log reduction category of \>= 4 to \<4.5 -log reduction (MR4); BCR-ABL ratio by percentage: \<=0.0032% is equal to a log reduction category of \>= 4.5-log reduction (MMR4.5)

Time from first study drug intake to first MMR amongst imatinib or dasatinib resistant or intolerant patients with CML-CP computed only for patients who achieved MMR.

Time to MMR is the time from first study drug intake to first major molecular response computed only for participants who achieved MMR.

Duration of MMR is defined as the time between the date of the first MMR and the date of confirmed loss of MMR (i.e. the earliest of confirmed loss of MMR, CML-related death or progression to AP or BC). Participants without loss of MMR were censored at the last molecular assessment date.

* Complete cytogenetic response (CCyR) - 0% Ph+ metaphases
* Partial cytogenetic response (PCyR) - \>0 to 35% Ph+ metaphases
* Minor cytogenetic response (mCyR) - \>35 to 65% Ph+ metaphases
* Minimal - \>65 to 95% Ph+ metaphases
* None - \>95 to 100% Ph+ metaphases
* Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

Complete cytogenetic response (CCyR) - 0% Ph+ metaphases No response - \>95 to 100% Ph+ metaphases

Cytogenetic response is assessed as the percentage of Philadelphia positive (Ph+) metaphases in the bone marrow. Complete Cytogenetic Response (CCyR) is defined as 0% of Ph+ metaphases. A patient was counted as having CCyR by 6 cycles (respectively 12 cycles) if the patient met the CCyR criteria at least once at any time between first study drug intake and cycle 6 (cycle 12 respectively) visit included.

Major cytogenetic response (MCyR) - 0 to 35% Ph+ metaphases. A major response combines both complete and partial responses.

Complete Hematological Response (CHR) was defined as

* WBC count \<10×109/L
* platelet count \<450×109/L
* basophils \<5%
* no blasts and promyelocytes in peripheral blood
* myelocytes+metamyelocytes \<5% in peripheral blood
* no evidence of extramedullary disease, including spleen and liver
* Assessment confirmation after at least 4 weeks for newly diagnosed Ph+ CML-CP

Time to disease progression is the time from the date of first study drug intake to the date of event defined as the first progression to AP or BC (from CP) or to BC (from AP) or the date of CML-related death occurring on treatment, whichever was earlier.

Event Free Survival is defined as the time from the date of first study drug intake to the first occurrence of any of the following loss of CHR, loss of MCyR ( PCyR + CCyR), progression to AP/BC (from CP) or to BC (from AP), or death from any cause. (Including events only during treatment)

Overall survival is defined as the time from the date of first study drug intake to the date of death due to any cause. If a patient is not known to have died, survival will be censored at the date of their last assessment for patients on study and date of last contact for patients in follow-up.

BCR-ABL is the fusion gene from breakpoint cluster region and Abelson genes. BCR-ABL transcript levels were summarized by cohort and time point. MMR is defined as ≤ 0.1% BCR-ABL/control gene (ABL) % by international scale, or equivalent to ≥ 3 log reduction of BCR-ABL transcript from standardized baseline, measured by RQ-PCR.

PK was analyzed only when all patients has completed 12 cycles on treatment or discontinued the study treatment early.

PK was analyzed only when all patients has completed 12 cycles of treatment or discontinued the study treatment early.

To assess long term effect on growth, development and maturation of nilotinib treatment in pediatric patients with Ph+ CML in participants with both a baseline and post-baseline value.

Acceptability of the study drug was evaluated from a questionnaire completed by patients, with the help from parents or caregivers at visits.

The Questionnaire to capture patient assessment of palatability (very good to very bad) and acceptability of taking the medication (very easy to very hard to administration).

Emerging signs of resistance to nilotinib

Adverse Event: Any sign or symptom that occurs during the study treatment plus the 30 days post treatment.

Patients resistant or intolerant to either imatinib or dasatinib

Resistant/Intolerant Ph+ CML in CP

Patients newly diagnosed in Chronic phase. Diagnosis within 6 months of date of first cytogenetic analysis confirming Philadelphia chromosome with (9;22) translocation by standard conventional cytogenetic analysis

Newly Diagnosed and Untreated Ph+ CML in First CP

All of the patients enrolled in the study.

All Patients

Total

1 to < 12 years

12 to < 18 years

Full Analysis Set (FAS): All patients who received at least one dose of study medication.

Age, Customized

Sex: Female, Male

Caucasian

Black

Asian

Native American

Other

Race/Ethnicity, Customized

Study Director

Full Analysis Set (FAS): All patients who received at least one dose of study medication

Rate of Major Molecular Response (MMR) at 6 Cycles for Ph+ CML CP Patients Resistant or Intolerant to Imatinib or Dasatinib

Patients newly diagnosed in Chronic phase. Diagnosis within 6 months of date of first cytogenetic analysis confirming Philadelphia chromosome with (9;22) translocation by standard conventional cytogenetic analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Phase I Study of AT13148, a Novel AGC Kinase Inhibitor	NCT01585701	Advanced Solid ...	AT13148	18 Years -	Cancer Research UK
Phase I Study of AT13148, a Novel AGC Kinase Inhibitor	NCT01585701	Advanced Solid ...	AT13148	18 Years -	Cancer Research UK
Phase I Study of AT13148, a Novel AGC Kinase Inhibitor	NCT01585701	Advanced Solid ...	AT13148	18 Years -	Cancer Research UK
A Study to Assess How Itraconazole Affects the Uptake and Elimination of Capivasertib in the Body	NCT04712396	Healthy Volunte...	Capivasertib Itraconazole	18 Years - 58 Years	AstraZeneca
Prospective Pilot Trial to Assess a Multimodal Molecular Targeted Therapy in Children, Adolescent and Young Adults With Relapsed or Refractory High-grade Pineoblastoma	NCT02596828	Pineoblastoma	Temozolomide Irinotecan Dasatinib Rapamycin	0 Years - 25 Years	University of Regensburg
Open Label, Phase II Study to Evaluate Efficacy and Safety of Oral Nilotinib in Philadelphia Positive (Ph+) Chronic Myelogenous Leukemia (CML) Pediatric Patients.	NCT01844765	Philadelphia Po...	nilotinib	1 Year - 17 Years	Novartis
Prospective Pilot Trial to Assess a Multimodal Molecular Targeted Therapy in Children, Adolescent and Young Adults With Relapsed or Refractory High-grade Pineoblastoma	NCT02596828	Pineoblastoma	Temozolomide Irinotecan Dasatinib Rapamycin	0 Years - 25 Years	University of Regensburg
Phase I Study of AT13148, a Novel AGC Kinase Inhibitor	NCT01585701	Advanced Solid ...	AT13148	18 Years -	Cancer Research UK
Multimodal Molecular Targeted Therapy to Treat Relapsed or Refractory High-risk Neuroblastoma	NCT01467986	Neuroblastoma R...	Dasatinib Rapamycin Irinotecan Temozolomide Irinotecan Temozolomide	- 25 Years	University of Regensburg
Hepatotoxicity Related to Protein Kinase Inhibitors	NCT05430126	Cancer	Protein Kinase ...	-	Central South University
A Study to Assess How Itraconazole Affects the Uptake and Elimination of Capivasertib in the Body	NCT04712396	Healthy Volunte...	Capivasertib Itraconazole	18 Years - 58 Years	AstraZeneca
Multimodal Molecular Targeted Therapy to Treat Relapsed or Refractory High-risk Neuroblastoma	NCT01467986	Neuroblastoma R...	Dasatinib Rapamycin Irinotecan Temozolomide Irinotecan Temozolomide	- 25 Years	University of Regensburg
Hepatotoxicity Related to Protein Kinase Inhibitors	NCT05430126	Cancer	Protein Kinase ...	-	Central South University

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