NeoplasmsPhase 1NCT02257476
Extended Infusion Carfilzomib on a Weekly Schedule in Patients With Advanced Solid Tumors
A Phase 1 study testing Carfilzomib and Dexamethasone in people with Neoplasms and Malignancies, run by Emory University at 1 site in United States.
Trial summary
The purpose of this study is to find the safest dose level of an approved drug, carfilzomib, in solid tumors when given over a different period of time than normally used. The study will also use markers in blood from routine blood draws to help check the levels of the drug. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Neoplasms, Malignancies
- What is being tested?
- Carfilzomib and Dexamethasone
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 22 participants
- Where
- 1 siteUnited States
- Study dates
- Aug 2014to Nov 2016
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Patient aged 18 years or older at the time of enrollment.
- Advanced/metastatic solid tumor refractory to standard therapy.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 - 2.
- Adequate organ function as assessed by the following:
- Bone marrow:
- Hemoglobin greater than or equal to 9.0 g/dL
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- Absolute neutrophil count (ANC) greater than or equal to 1,500/mm³
- Platelet count greater than or equal to 100,000/mm³
- Hepatic:
- Total bilirubin less than or equal to 1.5 x ULN
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x ULN
- Prothrombin time (PT)-international normalized ratio (INR)/partial thromboplastin time (PTT) < 1.5 x ULN except in patients receiving active anticoagulation
- Renal:
- Serum creatinine ≤ 1.5 x upper limit of normal or
- Glomerular filtration rate (GFR) of 50 ml/minute or greater (if elevated serum creatinine level > 1.5 x ULN)
- Willingness to sign informed consent by patient or patient's legal representative.
- Patient with known but adequately treated brain metastases and without central nervous system (CNS) disease progression as determined by CT or MRI imaging within 4 weeks of the first dose of study drug.
Who cannot join
- Treatment related residual toxicity > grade 1.
- Prior treatment with a proteasome inhibitor.
- Uncontrolled systemic disease or intercurrent illness.
- Recent history of myocardial infarction (MI) or symptomatic coronary artery disease within the preceding 6 months.
- History of uncontrolled hypertension (systolic > 150 mmHg or diastolic pressure > 90 mmHG despite optimal medical management).
- Ejection fraction < 50%.
Show all 17Show fewer
- Known and actively treated infection with human immunodeficiency virus (HIV), hepatitis B or C.
- Major surgery or significant traumatic injury within 4 weeks of first study treatment from which the subject has not fully recovered.
- Pregnant or breast feeding women.
- Female patient of child-bearing potential or male patient with partner of child-bearing potential but unable or unwilling to use effective contraception (double barrier such as condoms, contraceptive sponge, diaphragm or vaginal ring with spermicidal jellies or cream; or hormonal method such as oral, parenteral or transdermal hormonal agents for at least three months prior to study drug administration).
- Corticosteroid doses greater than equivalent of prednisone 7.5 mg PO daily.
- Recent therapy with any active anticancer agent within 4 weeks of the 1st dose of the study drugs.
- Any other current malignancy or previous malignancies within 3 years of enrollment except: curatively treated in situ carcinoma of the cervix uteri; localized basal or squamous cell carcinoma of the skin, curatively treated in situ breast carcinoma, and early stage prostate cancer.
- Known history of allergy to Captisol® (a cyclodextrin derivative used to solubilize carfilzomib).
- Contraindication to any of the required concomitant drugs or supportive treatments, including hypersensitivity to all anticoagulation and antiplatelet options, antiviral drugs, or intolerance to hydration due to preexisting pulmonary or cardiac impairment.
- Subjects with pleural effusions requiring thoracentesis or ascites requiring paracentesis within 14 days prior to randomization.
- Any other clinically significant medical disease or condition that, in the Investigator's opinion, may interfere with protocol adherence or a subject's ability to give informed consent.
Trial locations and contacts
1 site in 1 country.
United States1 site
Emory University Winship Cancer Institute
Atlanta, Georgia, 30322
About this study
Official title: A Phase I Study of Extended Infusion Carfilzomib on a Weekly Schedule in Patients With Advanced Solid Malignancies
The purpose of this study is to find the safest dose level of an approved drug, carfilzomib, in solid tumors when given over a different period of time than normally used. The study will also use markers in blood from routine blood draws to help check the levels of the drug. Lastly, the study will check how well this drug works with regards to keeping cancer cells from growing with the new time frame of delivery.
Read the detailed description
The role of the proteasome in carcinogenesis and cell survival has been well established, and its inhibition associated with an accumulation of pro-apoptotic proteins and cell death. Proteasome inhibitors, such has bortezomib, have been extensively studied and are widely used as effective therapy in the treatment for hematologic malignancies, such as multiple myeloma where circulating proteasome levels have been correlated with survival. Carfilzomib, a novel irreversible proteasome inhibitor which specifically targets the chymotryptic site of the proteasome has shown more potency than bortezomib and may be able to overcome bortezomib resistance. Response rates between 25-54% were seen in patients with previously treated myeloma in the phase 2 setting.
Given the effectiveness of proteasome inhibition in multiple myeloma, the role of proteasome in solid tumors is under active investigation. Previous trials of bortezomib in breast, prostate, lung, and pancreatic cancer have shown little activity of this agent in these diseases. Whether the lack of activity may be mechanistically related (bortezomib inhibits chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing (PGPH)-like activities of the proteasome), or a lack of potency in target inhibition, is unknown.
In a phase Ib/II study of 14 patients (phase I) and 51 patients (phase II) with advanced solid tumors, Rosen and colleagues noted single-agent activity with carfilzomib. Carfilzomib was dosed on days 1, 2, 8, 9, 15, and 16 of a 28 day cycle to a maximum of 12 cycles, with 20-36 mg/m² noted as the recommended phase 2 dose based on DLT data. A PR in both renal and small cell lung cancer, and stable disease > 16 weeks in mesothelioma, ovarian, renal, and non-small cell lung cancer was observed. The treatment was tolerable with the most common adverse events (AEs) including fatigue, headache, diarrhea, nausea and constipation.
Given the activity of carfilzomib seen in selected solid tumors, and unpublished data to suggest weekly dosing may result in a similar pharmacokinetic profile including AUC, the investigators propose to study the safety, tolerability, pharmacokinetics, and anti-tumor activity of carfilzomib monotherapy given on a weekly dosing schedule. Weekly dosing has the advantage of patient convenience, and if acceptable toxicity and pharmacokinetics, it allows for easier integration of this schedule into subsequent combination therapy clinical trials.
- Conditions
- Neoplasms, Malignancies
- Being tested
- Carfilzomib, Dexamethasone
- Keywords
- carfilzomib, advanced solid malignancies, advanced solid cancers, prostate, bladder, colon, breast, lung
- Medical subject headings
- Neoplasms
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
CarfilzomibDrug
Also called PR-171, Kyprolis
Carfilzomib will be given as an IV infusion over 4 hours. Subjects will remain at the clinic under observation for at least 1 hour following each dose of carfilzomib in Cycle 1 and following the dose on Cycle 2 Day 1. During these observation times, post dose IV hydration may be given at physician's discretion.
DexamethasoneDrug
Also called Decadron
Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses.
| Study group | Role | What they receive |
|---|---|---|
| Carfilzomib | Experimental | Patients will receive single agent carfilzomib on a weekly dosing schedule (days 1, 8, 15) in a 21 day cycle. The initial dose will be 20 mg/m² for cycle 1, day 1. Dose escalation will proceed in a standard 3+3 fashion with the requirement that dose escalation to the next level can only proceed if 0 of 3 or ≤ 1 of 6 patients experience a dose limiting toxicity (DLT). Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses. Receives: Drug: Carfilzomib; Drug: Dexamethasone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of a weekly 4-hour carfilzomib infusion in patients with advanced solid malignancies
Evaluate safety and tolerability of weekly dosed carfilzomib as assessed by using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v.4 criteria to determine DLTs, the MTD, and RP2D
Measured: Up to 18 months
Secondary outcomes (6)
Pharmacokinetics (PK) of escalating doses of weekly intravenous carfilzomib
Pharmacokinetic analysis (Tmax, Cmax, t1/2, AUC)
Measured: 1, 2, 4, 6, 8, 28 hours post-dose
Changes in pharmacodynamic (PD) biomarkers before and during treatment with carfilzomib using peripheral blood mononuclear cells (PBMC) and paired tumor biopsies
Pharmacodynamic (PD) evaluation of degree of 20S proteasomal inhibition in PBMC assays conducted at Emory University before treatment and at time of first restaging scan
Measured: Days 1, 2, 3, 8, 15, 21
Preliminary anti-tumor efficacy (objective response rate)
Objective Response Rate (CR + PR) by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria in patients who completed at least 2 cycles of protocol therapy
Measured: Up to 18 months
Preliminary anti-tumor efficacy (clinical benefit rate)
Clinical Benefit Rate (CR + PR + SD) by RECIST 1.1 criteria in patients who completed at least 2 cycles of protocol therapy
Measured: Up to 18 months
Preliminary anti-tumor efficacy (progression free survival)
Measured: Up to 18 months
Preliminary anti-tumor efficacy (overall survival)
Measured: Up to 18 months
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted6 Oct 2014 (estimated)
- Study startAug 2014
- Primary completionNov 2016
- Study completionNov 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for NeoplasmsStudies of the same condition, open and under way.
- More trials run by Emory UniversityThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 22 participants (actual)
Sponsor and investigators
- Lead sponsor
- Emory University
- Sponsor type
- University, hospital or other
- Collaborators
- Amgen
- Responsible party
- Principal investigator, Bradley Carthon MD, PhD, Emory University
- Investigators
- Bradley C. Carthon, MD, PhD, Principal investigator, Emory University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02257476
- Sponsor's protocol ID
- IRB00071307
- Other IDs
- WINSHIP2598-13
- Status last verified
- Feb 2017
- First submitted
- 26 Sep 2014
- Last updated
- 7 Feb 2017
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 7 Feb 2017. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Study of Extended Infusion Carfilzomib on a Weekly Schedule in Patients With Advanced Solid Malignancies
- ClinicalTrials.gov ID
- NCT02257476
- Acronym / sponsor ID
- IRB00071307
- Conditions
- Neoplasms, Malignancies
- Keywords
- carfilzomib, advanced solid malignancies, advanced solid cancers, prostate, bladder, colon, breast, lung
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 22 participants (actual)
- Lead sponsor
- Emory UniversityUniversity, hospital or other
- Collaborators
- Amgen
- Study start
- Aug 2014 (actual)
- Primary completion
- Nov 2016 (actual)
- Study completion
- Nov 2016 (actual)
- First posted
- 6 Oct 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The purpose of this study is to find the safest dose level of an approved drug, carfilzomib, in solid tumors when given over a different period of time than normally used. The study will also use markers in blood from routine blood draws to help check the levels of the drug. Lastly, the study will check how well this drug works with regards to keeping cancer cells from growing with the new time frame of delivery.
Detailed description
The role of the proteasome in carcinogenesis and cell survival has been well established, and its inhibition associated with an accumulation of pro-apoptotic proteins and cell death. Proteasome inhibitors, such has bortezomib, have been extensively studied and are widely used as effective therapy in the treatment for hematologic malignancies, such as multiple myeloma where circulating proteasome levels have been correlated with survival. Carfilzomib, a novel irreversible proteasome inhibitor which specifically targets the chymotryptic site of the proteasome has shown more potency than bortezomib and may be able to overcome bortezomib resistance. Response rates between 25-54% were seen in patients with previously treated myeloma in the phase 2 setting.
Given the effectiveness of proteasome inhibition in multiple myeloma, the role of proteasome in solid tumors is under active investigation. Previous trials of bortezomib in breast, prostate, lung, and pancreatic cancer have shown little activity of this agent in these diseases. Whether the lack of activity may be mechanistically related (bortezomib inhibits chymotrypsin-like and peptidyl-glutamyl peptide-hydrolyzing (PGPH)-like activities of the proteasome), or a lack of potency in target inhibition, is unknown.
In a phase Ib/II study of 14 patients (phase I) and 51 patients (phase II) with advanced solid tumors, Rosen and colleagues noted single-agent activity with carfilzomib. Carfilzomib was dosed on days 1, 2, 8, 9, 15, and 16 of a 28 day cycle to a maximum of 12 cycles, with 20-36 mg/m² noted as the recommended phase 2 dose based on DLT data. A PR in both renal and small cell lung cancer, and stable disease > 16 weeks in mesothelioma, ovarian, renal, and non-small cell lung cancer was observed. The treatment was tolerable with the most common adverse events (AEs) including fatigue, headache, diarrhea, nausea and constipation.
Given the activity of carfilzomib seen in selected solid tumors, and unpublished data to suggest weekly dosing may result in a similar pharmacokinetic profile including AUC, the investigators propose to study the safety, tolerability, pharmacokinetics, and anti-tumor activity of carfilzomib monotherapy given on a weekly dosing schedule. Weekly dosing has the advantage of patient convenience, and if acceptable toxicity and pharmacokinetics, it allows for easier integration of this schedule into subsequent combination therapy clinical trials.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Carfilzomib | Experimental | Drug: Carfilzomib, Drug: DexamethasonePatients will receive single agent carfilzomib on a weekly dosing schedule (days 1, 8, 15) in a 21 day cycle. The initial dose will be 20 mg/m² for cycle 1, day 1. Dose escalation will proceed in a standard 3+3 fashion with the requirement that dose escalation to the next level can only proceed if 0 of 3 or ≤ 1 of 6 patients experience a dose limiting toxicity (DLT). Dexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (17 listed)
- Patient aged 18 years or older at the time of enrollment.
- Advanced/metastatic solid tumor refractory to standard therapy.
- Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 - 2.
- Adequate organ function as assessed by the following:
- Willingness to sign informed consent by patient or patient's legal representative.
Key exclusion criteria (17 listed)
- Treatment related residual toxicity > grade 1.
- Prior treatment with a proteasome inhibitor.
- Uncontrolled systemic disease or intercurrent illness.
- Recent history of myocardial infarction (MI) or symptomatic coronary artery disease within the preceding 6 months.
- History of uncontrolled hypertension (systolic > 150 mmHg or diastolic pressure > 90 mmHG despite optimal medical management).
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| CarfilzomibAlso: PR-171, KyprolisCarfilzomib will be given as an IV infusion over 4 hours. Subjects will remain at the clinic under observation for at least 1 hour following each dose of carfilzomib in Cycle 1 and following the dose on Cycle 2 Day 1. During these observation times, post dose IV hydration may be given at physician's discretion. | Drug | Carfilzomib |
| DexamethasoneAlso: DecadronDexamethasone 8 mg PO/IV will be administered prior to all carfilzomib doses. | Drug | Carfilzomib |
Primary outcome
Maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of a weekly 4-hour carfilzomib infusion in patients with advanced solid malignancies
Time frame: Up to 18 months
Evaluate safety and tolerability of weekly dosed carfilzomib as assessed by using NCI Common Toxicity Criteria for Adverse Effects (CTCAE) v.4 criteria to determine DLTs, the MTD, and RP2D
6 secondary outcomes
Pharmacokinetics (PK) of escalating doses of weekly intravenous carfilzomib
Time frame: 1, 2, 4, 6, 8, 28 hours post-dose
Changes in pharmacodynamic (PD) biomarkers before and during treatment with carfilzomib using peripheral blood mononuclear cells (PBMC) and paired tumor biopsies
Time frame: Days 1, 2, 3, 8, 15, 21
Preliminary anti-tumor efficacy (objective response rate)
Time frame: Up to 18 months
Preliminary anti-tumor efficacy (clinical benefit rate)
Time frame: Up to 18 months
Preliminary anti-tumor efficacy (progression free survival)
Time frame: Up to 18 months
Preliminary anti-tumor efficacy (overall survival)
Time frame: Up to 18 months
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 7 Feb 2017.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Bradley C. Carthon, MD, PhD principal investigator
Emory University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Carfilzomib and Dexamethasone in people with Neoplasms and Malignancies, run by Emory University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 17 inclusion and 17 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 7 Feb 2017. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of a weekly 4-hour carfilzomib infusion in patients with advanced solid malignancies (time frame: Up to 18 months). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 7 Feb 2017.