Neoplasms

Heart and Blood Diseases

Blood and Lymph Conditions

Immune System Diseases

All Conditions

Rare Diseases

Multiple Myeloma

Neoplasms, Plasma Cell

Neoplasms by Histologic Type

Hemostatic Disorders

Blood Coagulation Disorders

Vascular Diseases

Paraproteinemias

Blood Protein Disorders

Hematologic Diseases

Hemorrhagic Disorders

Lymphoproliferative Disorders

Immunoproliferative Disorders

Approximately 8 subjects will receive Afuresertib 125 mg daily starting Cycle 1 Day 2 + Carfilzomib 20 mg/m\^2: Cycle 1, Day 1, 2; Cycle 2, Day 1. Carfilzomib 27 mg (increased dosage of 27 mg/meter (m)\^2 will be administered only if tolerated): Cycle 1, Days 8, 9, 15, and 16; Cycle 2, Days 2, 8, 9, 15, and 16; Cycle 3 and onwards, Days 1, 2, 8, 9, 15, and 16 of each cycle

Approximately 8 subjects will receive oral Afuresertib 150 mg daily starting Cycle 1 Day 2 + Carfilzomib 20 mg/m\^2: on Cycle 1, Day 1, 2; Cycle 2, Day 1. Carfilzomib 27 mg/m\^2 (increased dosage of 27 mg/m\^2 will be administered only if tolerated): Cycle 1, Days 8, 9, 15, and 16; Cycle 2, Days 2, 8, 9, 15, and 16; Cycle 3 and onwards, Days 1, 2, 8, 9, 15, and 16 of each cycle

An additional arm with 100 mg of afuresertib may be evaluated if the other 2 arms are not tolerated. Approximately 8 subjects will receive Afuresertib 100 mg daily starting Cycle 1 Day 2 + Carfilzomib 20 mg/m\^2: on Cycle 1, Day 1, 2; Cycle 2, Day 1. Carfilzomib 27 mg/m\^2 (increased dosage of 27 mg/m\^2 will be administered only if tolerated): Cycle 1, Days 8, 9, 15, and 16; Cycle 2, Days 2, 8, 9, 15, and 16; Cycle 3 and onwards, Days 1, 2, 8, 9, 15, and 16 of each cycle

Approximately 50 subjects will receive Afuresertib Recommended Phase 2 Dose (RP2D) daily starting Cycle 1 Day 1 + Carfilzomib 20 mg/m\^2 Cycle 1, Day 1, 2. Carfilzomib 27 mg (increased dosage of 27 mg/m\^2 will be administered only if tolerated): Cycle 1, Days 8, 9, 15 and 16; Cycle Days 1, 2, 8, 9, 15 and 16 of each cycle; Cycle 3 and onwards, Days 1, 2, 8, 9 and 15 and 16 of each cycle.

Approximately 50 subjects will receive Carfilzomib 20 mg/m\^2: Cycle 1, Day 1, 2. Carfilzomib 27 mg/m\^2 (increased dosage of 27 mg/m\^2 will be administered only if tolerated): Cycle 1, Days 8, 9 15, and 16; Cycle 2, Days 1, 2, 8, 9, 15 and 16 of each cycle; Cycle 3 and onwards, Days 1, 2, 8, 9, 15 and 16 of each cycle.

Afuresertib will be dosed orally in morning, and will be sourced as opaque, white, size 4, 25 mg capsule and size 1, 100 mg capsules.

Afuresertib

Intravenous (IV) Carfilzomib will be sourced in the US from commercial stock. It will be a single-use 60 mg vial as a sterile, white to off-white lyophilized cake or powder

Carfilzomib

Novartis Pharmaceuticals

This open-label, 2-part Phase I/ randomized Phase II multi-center study is conducted to evaluate the safety, tolerability, pharmacokinetics (PK), and clinical activity of afuresertib in combination with carfilzomib versus carfilzomib alone, in subjects with relapsed/refractory MM. Part 1 will evaluate 2 dose levels (125 milligrams \[mg\] and 150 mg of afuresertib) in 16 subjects (approximately 8 in each parallel arm) to determine an optimal dose of afuresertib for administration in combination with carfilzomib in Part 2. If neither of these dose levels are tolerated, an additional dose level of 100mg of afursertib in combination with carfilzomib may be explored in approximately 8 additional subjects. Part 2 was to investigate the safety, and clinical activity of the combination of afuresertib with carfilzomib (determined in Part 1) compared to carfilzomib alone, in approximately 100 subjects (50 in each parallel arm), however the study was terminated after the discontinuation of the single subject following the transition of the afuresertib development program from GSK to Novartis. The reason for the study termination is that the protocol defined study treatment was no longer aligned with the evolving standard of care.

A Study Conducted in Subjects With Relapsed/Refractory Multiple Myeloma (MM); to Determine Dose of Afuresertib in Combination With Carfilzomib (Part 1) and to Investigate the Safety, Pharmacokinetic and Clinical Activity of the Combination Compared With Carfilzomib Alone (Part 2)

An Open Label, Two-part, Phase I/Randomized Phase II Study in Subjects With Relapsed/Refractory Multiple Myeloma to Determine a Dose of Afuresertib for Administration in Combination With Carfilzomib (Part 1) and to Investigate the Safety, Pharmacokinetics, and Clinical Activity of the Combination of Afuresertib With Carfilzomib Compared With Carfilzomib Alone (Part 2)

AEs and serious adverse events (SAEs) will be collected from the screening until the follow-up visit

Vital signs assessments included temperature, systolic and diastolic blood pressure, temperature and pulse rate measurements

Clinical laboratory parameters will include hematology and clinical chemistry

Single 12-lead ECGs will be obtained over a brief recording period at the start of each cycle

PFS defined as the interval between the date of randomization and the earliest date of disease progression as assessed by investigator or death due to any cause

Peripheral blood will be collected to evaluate PK parameters for Afuresertib (e.g., area under the plasma drug concentration-time curve \[AUC\], maximum observed plasma drug concentration \[Cmax\]) and carfilzomib (e.g., AUC, Cmax)

Afuresertib concentrations will be assessed in peripheral blood using a sparse sampling strategy

ORR is defined as the percentage of subjects with a confirmed stringent complete response (sCR), complete response (CR), very good partial response (VGPR), or partial response (PR), as assessed by investigator using the 2011 recommendations in the International Myeloma Workshop Consensus (IMWC) Panel 1

PFS is defined as the interval between the date of first dose and the earliest date of disease progression as assessed by investigator or death due to any cause

OS is defined as the time until death due to any cause. Subjects will be followed for up to a maximum of 12 months following the LSLD. Subjects who are alive at 12 months following the LSLD will be censored for OS

DOR defined for those subjects that achieve ORR as the time from first documented evidence of sCR, CR, VGPR, or PR until first documented disease progression or death

ORR defined as the percentage of subjects with a confirmed sCR, CR, VGPR or PR, as assessed by investigator using the 2011 recommendations in the IMWC Panel 1

AEs and SAEs will be collected from the screening until the follow-up visit

Single 12-lead ECGs will be obtained over a brief recording period at the start of each cycle.

Amgen

Novartis

Symptoms and General Pathology

Gland and Hormone Related Diseases

Recurrence

Adrenocortical Carcinoma

Adrenal Cortex Neoplasms

Carcinoma

Adrenal Gland Neoplasms

Endocrine Gland Neoplasms

Adrenal Cortex Diseases

Adrenal Gland Diseases

Endocrine System Diseases

Adenocarcinoma

Neoplasms, Glandular and Epithelial

Vasoconstrictor Agents

Respiratory System Agents

All Drugs and Chemicals

Antineoplastic Agents

Epinephrine

Axitinib

Racepinephrine

Epinephryl borate

Protein Kinase Inhibitors

Enzyme Inhibitors

Aggressive cancer that starts in the adrenal gland located at the top of the kidneys.

5 mg tab orally twice a day with food every 28 days

Antonio T Fojo, M.D.

Background:

- Adrenocortical carcinoma is an aggressive cancer that starts in the adrenal gland at the top of the kidneys. It has a low survival rate if standard treatment options are not effective. Axitinib is an experimental drug that is being studied to determine if it can stop tumors from growing or make them smaller. Researchers are interested in investigating axitinib in individuals with aggressive or otherwise untreatable adrenocortical cancer.

Objectives:

- To evaluate the effectiveness of axitinib in individuals who have adrenocortical cancer that is inoperable and has not responded to standard treatments.

Eligibility:

- Individuals at least 18 years of age who have been diagnosed with adrenocortical cancer that has not responded to standard treatments.

Design:

* Participants will be screened with a full physical examination and medical history, as well as tumor imaging studies.
* Participants may have a tumor biopsy prior to starting axitinib.
* All participants will receive axitinib to take twice a day with food for 28 days (1 cycle). Participants should not drink grapefruit juice or smoke cigarettes while participating in this study.
* After the first cycle, the dose may be increased and additional cycles will be given if the treatment has not had serious side effects.
* Participants will have regular examinations while taking axitinib, including blood samples and tumor imaging studies to determine if the tumor has stopped growing. Blood pressure levels will be carefully monitored during treatment to evaluate potential risk for high blood pressure.
* Participants may have a second tumor biopsy 20 to 30 days after treatment begins.
* Treatment will continue as directed by the study researchers.

Background:

* The response rates of recurrent, metastatic and unresectable adrenocortical cancer (ACC) to mitotane, doxorubicin, etoposide, and cisplatin are low and underscore the need for more effective systemic therapies.
* VEGF expression and evidence of angiogenesis has been found in many ACCs, so it is plausible that interfering with vascular endothelial growth factor(VEGF) signaling may result in anti-tumor activity in patients with ACC.
* Axitinib (AG-013736) is an oral, potent and selective inhibitor of vascular endothelial growth factor (VEGF) receptors 1, 2, and 3. Pre-clinical data suggests that the anti-tumor activity of axitinib may result from its anti-angiogenic activity and that this is reversible when treatment is discontinued.
* Given the known clinical safety and efficacy of axitinib, an assessment of its activity in ACC and its impact on the VEGF pathway in ACC could provide valuable information.

Objectives:

* Determine the response rate of axitinib (AG-013736) in recurrent, metastatic, or primary unresectable ACC
* Determine the progression-free survival
* Explore the relationship of potential biological markers of axitinib activity with clinical outcomes.
* Explore the pharmacogenetic analyses of drug metabolism and transport proteins through germline deoxyribonucleic acid (DNA) examination.

Eligibility:

* Adults with pathologic confirmation of ACC by the Laboratory of Pathology, National Cancer Institute (NCI)
* Diagnosis of recurrent, metastatic, or primary unresectable ACC
* Measurable disease at presentation
* Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
* Patients must not have received prior therapy with a tyrosine kinase (TK) inhibitor

Design:

* Phase II, open label, non-randomized trial
* Patients with recurrent, metastatic, or primary unresectable ACC will be given in eight weeks cycles with BID dosing of axitinib (AG-013736).
* Patients will be evaluated for response every eight weeks using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
* Tumor biopsies are not mandatory but every attempt will be made to obtain these from patients prior to starting axitinib and again 20-30 days after treatment has begun.
* Approximately 40 patients will be needed to achieve the objectives of the trial.

Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-Pathway in Metastatic, Recurrent or Primary Unresectable Adrenocortical Cancer

Response was defined by the Response Evaluation Criteria in Solid Tumors (RECIST). Complete response (CR) is a disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10mm. Partial response (PR) is at least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameter. Progressive disease (PD) is a 20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of at least 5mm (Note: the appearance of one or more new lesions is also considered progression). Stable disease (SD) is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking s reference the smallest sum diameters while on study.

Here is the number of participants with adverse events. For a detailed list of adverse events, see the adverse events module.

Pfizer

National Cancer Institute (NCI)

Aggressive cancer that starts in the adrenal gland located at the top of the kidneys.

Axitinib : 5 mg tab orally twice a day with food every 28 days

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Study Conducted in Subjects With Relapsed/Refractory Multiple Myeloma (MM); to Determine Dose of Afuresertib in Combination With Carfilzomib (Part 1) and to Investigate the Safety, Pharmacokinetic and Clinical Activity of the Combination Compared With Carfilzomib Alone (Part 2)	NCT02235740	Cancer	Afuresertib Carfilzomib	18 Years -	Novartis
Phase II Study of Axitinib (AG-013736) With Evaluation of the VEGF-Pathway in Metastatic, Recurrent or Primary Unresectable Adrenocortical Cancer	NCT01255137	Adrenal Cortex ...	Axitinib	18 Years - 80 Years	National Institutes of Health Clinical Center (CC)
A Study Conducted in Subjects With Relapsed/Refractory Multiple Myeloma (MM); to Determine Dose of Afuresertib in Combination With Carfilzomib (Part 1) and to Investigate the Safety, Pharmacokinetic and Clinical Activity of the Combination Compared With Carfilzomib Alone (Part 2)	NCT02235740	Cancer	Afuresertib Carfilzomib	18 Years -	Novartis

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