Renal Cell Carcinoma
Conditions
Keywords
Renal Cell Carcinoma
Brief summary
This research study is investigating a drug as a possible treatment for metastatic renal cell carcinoma. The intervention involved in this study is TAK-228.
Detailed description
This research study is a Phase II clinical trial. Phase II clinical trials test the safety and effectiveness of an investigational intervention to learn whether the intervention works in treating a specific disease. Investigational means that the intervention is being studied. The FDA (the U.S. Food and Drug Administration) has not approved TAK-228 as a treatment for any disease but it is being investigated as a treatment for advanced solid tumors, blood disorders, and inflammatory diseases. TAK-228 works to inhibit or interfere with cellular functions involved in cell growth and survival. TAK-228 specifically targets a type of protein that can make chemicals that trigger cell growth, including cancer cell growth. This protein may also cause cells to produce proteins that trigger the development of new blood vessels. Cancers need new blood vessels in order to grow. In some types of cancer, this type of protein (mTOR) is switched on, and it makes the cancer cells grow and produce new blood vessels. mTOR blockers (inhibitors) are a newer type of cancer growth blocker that can stop the growth of some types of cancer. Researchers hope to learn how participants with previously treated mRCC will respond to treatment with TAK-228. Other goals of this study include assessing the types of side effects associated TAK-228 and whether there is a relationship between certain genetic mutations (changes to your DNA) and participant responses to the drug.
Interventions
DRUGTAK-228
TAK-228 works to inhibit or interfere with cellular functions involved in cell growth and survival. TAK-228 specifically targets a type of protein that can make chemicals that trigger cell growth, including cancer cell growth
Sponsors
Calithera Biosciences, Inc
Bradley A. McGregor, MD
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥ 18 years. * Measurable disease according to RECIST 1.1 within 28 days prior to registration. * Documented pathologic diagnosis of RCC. All subtypes eligible including but not limited to clear cell, papillary, chromophobe, collecting duct carcinoma, medullary carcinoma, and unclassified categories. Sarcomatoid and rhabdoid differentiation are allowed. * Patients with clear cell histology must have demonstrated: 1) Progression on at least one prior anti -angiogenic agent unless intolerable; AND 2) progression on at least one agent that blocks the PD-1 pathway unless felt by the treating physician to be contraindicated (examples include but are not limited to: patients with autoimmune disease or patients requiring systemic steroids greater than 10 mg/day prednisone or its equivalent) or if they have been discontinued due to toxicity. Prior rapalogues are allowed. * Patients with non-clear cell histology must have received at least one prior anti-cancer therapy. Prior rapalogues are allowed. * Left ventricular ejection fraction (LVEF) ³ lower limit of normal (LLN) as assessed by either multigated acquisition (MUGA) scan or echocardiogram (ECHO). * Eastern Cooperative Oncology Group (ECOG) performance status of 0-2. * Must have adequate organ and bone marrow function. * Hematological * Absolute Neutrophil Count (ANC) ≥ 1500 K/mm\^3 (without use of G-CSF 4 weeks prior to enrollment) * Hemoglobin (Hgb) ≥ 9 g/dL (transfusions allowed) * Platelets (Plts) ≥ 100 k/mm\^3 * Renal * Calculated creatinine clearance (Cockcroft-Gault formula will be used to calculate creatinine clearance) ≥ 30 mL/min * Urinalysis: For patients with 2+ proteinuria on urinalysis, 24 hour urine collection should be obtained, 24 hour urine protein should be \<2 grams. * Hepatic * Bilirubin ≤ 1.5 × upper limit of normal (ULN). For subjects with Gilbert's disease ≤ 3.0 mg/dL * Aspartate aminotransferase (AST) ≤ 2.5 × ULN; ≤ 5 x ULN if liver metastases are present * Alanine aminotransferase (ALT) ≤ 2.5 × ULN; ≤ 5 x ULN if liver metastases are present * Metabolic * Glycosylated hemoglobin (HbA1c) \< 7.0%, * Fasting serum glucose ≤ 130 mg/dL * Fasting triglycerides ≤ 300 mg/dL * Recovery to baseline or ≤ grade 1 Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 from toxicities related to any prior treatment, unless adverse events are clinically non-significant and/or stable on supportive therapy. * Capable of understanding and complying with the protocol requirements and has signed the informed consent document. Voluntary written consent must be given before performance of any study related procedure not part of standard medical care, with the understanding that consent may be withdrawn by the subject at any time without prejudice to future medical care. * Submission of formalin-fixed, paraffin-embedded (FFPE) archival tumor specimens from the previous 18 months, if available. If not available, a fresh tumor biopsy prior to treatment initiation is MANDATORY unless determined medically unsafe or not feasible by the site investigator. * The archival specimen must contain adequate viable tumor tissue. * Specimens may consist of a tissue block (preferred and should contain the highest grade of tumor) or a recommended minimum of 20 unstained serial sections. Fine-needle aspiration, brushings, cell pellet from pleural effusion, bone marrow aspirate/biopsy are not acceptable. * Distant metastases specimens are preferred but if not available primary nephrectomy specimens are acceptable. * Subjects who experience a disease response per RECIST 1.1 criteria followed by subsequent progression will be required to have a post-treatment biopsy if feasible and safe. * Sexually active subjects and their partners must agree to use medically accepted methods of contraception. * For women: * Postmenopausal for at least 1 year before the screening visit, OR * Surgically sterile, OR * Agree to practice 1 effective method of contraception and 1 additional effective (barrier) method at the same time, from the time of signing the informed consent through 90 days (or longer, as mandated by local labeling \[eg. USPI, SmPC, etc.\] after the last dose of study drug, OR * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject (Periodic abstinence \[e.g, calendar, ovulation, symptothermal, postovulation methods\] and withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) * For men: * Even if surgically sterilized (ie, status post-vasectomy), they must agree to practice highly effective barrier contraception during the entire study treatment period and through 120 days after the last dose of study drug, OR * Agree to practice true abstinence, when this is in line with the preferred and usual lifestyle of the subject (Periodic abstinence \[e.g, calendar, ovulation, symptothermal, postovulation methods for the female partner\] and withdrawal, spermicides only, and lactational amenorrhea are not acceptable methods of contraception. Female and male condoms should not be used together.) * Agree not to donate sperm during the course of this study or 120 days after receiving their last dose of study drug
Exclusion criteria
* Subjects with a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 6 months of study treatment initiation. * Receipt of any type of small molecular kinase inhibitor (including investigational kinase inhibitors) within 2 weeks of enrollment or receipt of any anti-cancer therapy (including investigational therapy, monoclonal antibodies, cytokine therapy) within 3 weeks of enrollment. * Treatment with any investigational products within 3 weeks before the first dose of study drug. * Radiation therapy for bone metastases within 2 weeks, other external radiation therapy within 4 weeks of enrollment. * Received prior hemibody external radiotherapy. * Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy, radiosurgery, or surgery and stable for at least 4 weeks prior to enrollment as documented by magnetic resonance imaging (MRI) or computed tomography (CT) imaging. Treated brain metastases are defined as having no ongoing requirement for steroids and no evidence of progression or hemorrhage after treatment for at least 4 weeks prior to enrollment as documented by MRI or CT imaging. * Imminent or established spinal cord compression based on clinical and/or imaging. In subjects with untreated imminent or established spinal cord compression, treatment with standard of care as clinically indicated should be completed at least 4 weeks before enrollment. * The subject has a history of any of the following within the last 6 months before administration of the first dose of the drug: * Ischemic myocardial event, including angina requiring therapy and artery revascularization procedures * Ischemic cerebrovascular event, including transient ischemic attack and artery revascularization procedures * Requirement for inotropic support (excluding digoxin) or serious (uncontrolled) cardiac arrhythmia (including atrial flutter/fibrillation, ventricular fibrillation or ventricular tachycardia) * Placement of a pacemaker for control of rhythm * New York Heart Association (NYHA) Class III or IV heart failure * Significant active cardiovascular or pulmonary disease including: * Uncontrolled hypertension defined as sustained BP \>160 mm Hg systolic or \> 95 mm Hg diastolic despite optimal antihypertensive treatment. * Pulmonary hypertension * Uncontrolled asthma or O2 saturation \< 90% by arterial blood gas analysis or pulse oximetry on room air * Significant valvular disease; severe regurgitation or stenosis by imaging independent of symptom control with medical intervention, or history of valve replacement * History of arrhythmia requiring an implantable cardiac defibrillator * Medically significant (symptomatic) bradycardia * Poorly controlled diabetes mellitus defined as glycosylated hemoglobin (HbA1c) \> 7%; subjects with a history of transient glucose intolerance due to corticosteroid administration may be enrolled in this study if all other inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Best Overall Response Rate | Imaging assessments occurred every eight weeks (2 cycles) for response evaluation. The median number of cycles administered was 2 (range <1-15), thus participants were assessed up to ~14 months. | The best overall response rate is the percentage of participants achieving complete response (CR) or partial response (PR) as the best response recorded on treatment based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). CR and PR must meet the following lesion criteria without having any new lesions as well: Target Lesion: (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Non-Target Lesion: (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). Non-CR/Non-Progressive Disease: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have PR in target lesion. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Median Progression Free Survival | Participants followed for up to 14 months | Progression free survival (PFS) was defined as time from treatment initiation to radiographic progression, clinical progression or death from any cause, or it was censored at the date of last disease evaluation if an event had not occurred. Median PFS was estimated from the Kaplan Meier methodology. Radiographic progression is defined by Response Evaluation Criteria In Solid Tumors Criteria 1.1 as follows: \- \>20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including baseline if it's the smallest). OR -Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. |
| Median Overall Survival | Participants were follow for up to ~27 months | Overall survival was defined as the time from treatment initiation to death from any cause or censored at the time of last follow-up for surviving patients. Median overall survival was estimated using the Kaplan Meier methodology. |
| Percentage of Participants With Any Grade 3 or Higher Treatment-related Adverse Events | Adverse events are measured continuously on treatment and up to thirty days after going off treatment (up to ~15 months). | Toxicity was assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment related adverse events were those that were deemed as Definitely, Probably and Possibly related to the study treatment. |
Countries
United States
Participant flow
Recruitment details
39 patients were enrolled from 8 institutions between August 2017 and November 2019.
Pre-assignment details
1 patient was deemed as ineligible and did not receive protocol treatment. 38 eligible and treated patients were included in the analysis.
Participants by arm
| Arm | Count |
|---|---|
| TAK228 Subjects will receive treatment with TAK-228 30mg by mouth weekly on day 1, 8, 15 and 22 of a 28-day cycle. Dose can be reduced by the study team. Treatment will continue until disease progression, unaccepted toxicity or other reasons for discontinuation defined by protocol. | 38 |
| Total | 38 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Ineligible for Study Drug | 1 |
| Overall Study | Patient Decision | 1 |
| Overall Study | Physician Decision | 1 |
| Overall Study | Progressive Disease | 29 |
| Overall Study | Still on Therapy | 2 |
| Overall Study | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | TAK228 |
|---|---|
| Age, Continuous | 62 years |
| Histology Clear cell histology | 28 Participants |
| Histology Non clear cell histology | 10 Participants |
| Prior rapalogs treatment No | 21 Participants |
| Prior rapalogs treatment Yes | 17 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 2 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 36 Participants |
| Sex: Female, Male Female | 5 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 15 / 38 |
| other Total, other adverse events | 38 / 38 |
| serious Total, serious adverse events | 12 / 38 |
Outcome results
Primary
Best Overall Response Rate
The best overall response rate is the percentage of participants achieving complete response (CR) or partial response (PR) as the best response recorded on treatment based on Response Evaluation Criteria In Solid Tumors Criteria (RECIST 1.1). CR and PR must meet the following lesion criteria without having any new lesions as well: Target Lesion: (CR): Disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. (PR): At least a 30% decrease in the sum of the diameters of target lesions, taking as reference the baseline sum diameters. Non-Target Lesion: (CR): Disappearance of all non-target lesions and normalization of tumor marker level. All lymph nodes must be non-pathological in size (\<10 mm short axis). Non-CR/Non-Progressive Disease: Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the normal limits. Must have PR in target lesion.
Time frame: Imaging assessments occurred every eight weeks (2 cycles) for response evaluation. The median number of cycles administered was 2 (range <1-15), thus participants were assessed up to ~14 months.
Population: Best overall response was assessed in 38 eligible and treated patients. 1 patient who was deemed as ineligible and did not receive treatment was excluded from response analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| TAK-228 | Best Overall Response Rate | 5 percentage of participants |
Secondary
Median Overall Survival
Overall survival was defined as the time from treatment initiation to death from any cause or censored at the time of last follow-up for surviving patients. Median overall survival was estimated using the Kaplan Meier methodology.
Time frame: Participants were follow for up to ~27 months
Population: Overall survival was assessed in 38 eligible and treated patients. 1 patient who was deemed as ineligible and did not receive treatment was excluded from analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TAK-228 | Median Overall Survival | 11.2 months |
Secondary
Median Progression Free Survival
Progression free survival (PFS) was defined as time from treatment initiation to radiographic progression, clinical progression or death from any cause, or it was censored at the date of last disease evaluation if an event had not occurred. Median PFS was estimated from the Kaplan Meier methodology. Radiographic progression is defined by Response Evaluation Criteria In Solid Tumors Criteria 1.1 as follows: \- \>20% increase in the sum of the diameters of target lesions, taking as reference the smallest sum on study (including baseline if it's the smallest). OR -Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions.
Time frame: Participants followed for up to 14 months
Population: Progression free survival was assessed in 38 eligible and treated patients. 1 patient who was deemed as ineligible and did not receive treatment was excluded from analysis.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| TAK-228 | Median Progression Free Survival | 2.5 months |
Secondary
Percentage of Participants With Any Grade 3 or Higher Treatment-related Adverse Events
Toxicity was assessed by Common Terminology Criteria for Adverse Events (CTCAE) version 4.0. Treatment related adverse events were those that were deemed as Definitely, Probably and Possibly related to the study treatment.
Time frame: Adverse events are measured continuously on treatment and up to thirty days after going off treatment (up to ~15 months).
Population: Adverse events were assessed in 38 eligible and treated patients. 1 patient who was deemed as ineligible and did not receive treatment was excluded from analysis.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| TAK-228 | Percentage of Participants With Any Grade 3 or Higher Treatment-related Adverse Events | Number of subjects who experienced grade 3 or higher adverse events | 12 Participants |
| TAK-228 | Percentage of Participants With Any Grade 3 or Higher Treatment-related Adverse Events | Number of subjects who did not experience grade 3 or higher adverse events | 26 Participants |