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Trial registered on ANZCTR


Registration number
ACTRN12614001292662
Ethics application status
Approved
Date submitted
28/11/2014
Date registered
11/12/2014
Date last updated
21/12/2017
Type of registration
Prospectively registered

Titles & IDs
Public title
Dose finding study for CRLX301 in solid tumors
Scientific title
Phase 1/2a Dose-Escalation Study of CRLX301 in Patients with Advanced Solid Tumor Malignancies
Secondary ID [1] 285753 0
CLRX301-101
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Solid Tumours 293639 0
Taxane-naive castration resistant prostate cancer (CRPC) 300734 0
Condition category
Condition code
Cancer 293935 293935 0 0
Other cancer types
Cancer 300566 300566 0 0
Prostate

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
All participants will receive an intravenous infusion of CRLX301 once every 3 weeks or once a week.
The dosage of CRLX301 will be dependent on the cohort to which the participant is recruited. In Phase I, participants will be recruited to dose escalation cohorts in a step wise manner at increasing doses of CRLX301 until MTD (maximum tolerated dose). Provisional doses are:

Schedule 1 (once every 3 weeks dosing)
Cohort 1: 7.5 mg/m2
Cohort 2: 15 mg/m2
Cohort 3: 30* mg/m2
Cohort 4: 45* mg/m2
Cohort 5: 60 mg/m2
Cohort 6: 75 mg/m2
Cohort 7: 90 mg/m2
Cohort 8: 105 mg/m2
Cohort 9: 120 mg/m2
Cohort 10 (plus additional cohorts): 135 mg/m2 (increase dose levels by 15 mg/m2 for additional cohorts)
*The Safety Review Committee (SRC) is allowed to dose escalate from 30 mg/m2 to as high as 60 mg/m2.

Schedule 2 (once a week dosing)
Cohort -1: 20 mg/m2
Cohort 1: 25 mg/m2
Cohort 2: 30 mg/m2
Cohort 3: 35 mg/m2
Cohort 4: 40 mg/m2
Cohort 5: 45 mg/m2
Cohort 6: 50 mg/m2
Additional cohorts: increase dose levels by 5 mg/m2 for additional cohorts or as recommended by SRC

In Phase 2a, all subjects will be treated at the dose determined in Phase 1 and cohort recruitment will be dependent on tumor type.

Treatment continues until progression of disease, dose limiting toxicity, or other protocol specified reason for study discontinuation.
Intervention code [1] 290714 0
Treatment: Drugs
Comparator / control treatment
Not applicable
Control group
Uncontrolled

Outcomes
Primary outcome [1] 293709 0
To determine the recommended Phase 2 dose (RP2D) of CRLX301 when administered by intravenous (IV) infusion once every 3-weeks or once a week dosing in patients with advanced solid tumor malignancies. This will be assessed by monitoring participants for dose-limiting adverse events (e.g. severely low white blood cell count, elevated liver function tests).
Timepoint [1] 293709 0
End of phase 1 (Dec2015- Jul2016)
Primary outcome [2] 293710 0
To further establish the safety and tolerability of the CRLX301 MTD / RP2D. This will be assessed by monitoring participants adverse events, laboratory tests, vital signs and electrocardiogram. Examples of adverse events could include: decrease in white blood cells, decrease in red blood cells.
Timepoint [2] 293710 0
End of phase 2 (Jan 2017- July 2017). Patients will be monitored for 30 days post last dose of study drug.
Secondary outcome [1] 311645 0
To evaluate the pharmacokinetic (PK) profile of CRLX301 in blood and urine specimens.
Timepoint [1] 311645 0
Blood samples will be collected at:
3-weekly dosing schedule- prior to CRLX301 infusion, 30 and 60 minutes during infusion, 30, 60, 180, 360 minutes after infusion, 1, 2, 7, 14, 21 days after infusion at Cycles 1, 3 and 6. Urine samples will be collected on Day 1 and day 8 of Cycles 1, 3 and 6.
Weekly dosing schedule- prior to CRLX301 infusion, 30 and 60 minutes during infusion, 30, 60, 180, 360 minutes after infusion and 1 day after infusion at weeks 1, 4 and 7. Prior to CRLX301 infusion at weeks 2, 3, 5 and 6.
Urine samples will be collected on Day 1 of weeks 1, 2, 4, 5, 7 and 8.
Secondary outcome [2] 311646 0
To explore preliminary signs of efficacy of CRLX301. This will be assessed via imaging or methodologies consistent with specific tumour type, performed periodically during the study.
Timepoint [2] 311646 0
Every 9 weeks.
Patients will be monitored for the entire duration they are on treatment- until progression of disease, Dose Limiting Toxicity, or other protocol specified reason for study discontinuation

Eligibility
Key inclusion criteria
1. Male or female adult patients older than or equal to 18 years of age
2. Diagnosis of histologically or cytologically confirmed, advanced solid tumour malignancy:
a) For Phase 1: that is refractory to standard therapy and/or for whom no further standard therapy is available, especially for those for whom taxane chemotherapy may be a reasonable therapeutic choice, in the opinion of the Investigator.
b) For Phase 2a: advanced/metastatic tumours considered responsive to taxanes
c) For prostate cancer patients in Phase 2a: that is castration resistant prostate cancer (CRPC*) and has not been previously treated with taxanes but has been treated with abiraterone and/or enzalutamide.
3. For patients enrolled in Phase 2a only: at least one measurable target lesion as defined by RECIST 1.1 criteria for solid tumours, except for patients with advanced prostate cancer (in which case as per the PCWG2 criteria). Tumours within a previously irradiated field should be designated as “non-target” unless progression is documented or a biopsy is obtained to confirm persistence at least 90 days following completion of radiation therapy.
4. If Patient has received:
a) approved chemotherapy or small molecule targeted therapy; it has been at least 2 weeks since last dose before CRLX301 first dose.
b) investigational therapy; it has been more than 30 days before first dose
c) local palliative radiation; it has been more than 14 days prior to first dose
d) radiation or invasive surgery requiring general anesthesia; it has been more than 30 days prior to first dose
e) chemotherapy with nitrosoureas or mitomycin C; it has been more than 45 days before first dose
5. ECOG Performance Status of 0 or 1
6. Life expectancy in opinion of Investigator of more than 12 weeks
7. Patients with acceptable pre-study hematology and biochemistry labs less than 72 hours prior to first dose
8. Fertile males or females of childbearing potential agree to use adequate contraception prior to study entry and for 30 days following last dose of study drug
9. Negative urine pregnancy test less than 72 hours prior to first dose (women of childbearing potential Only)
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Uncontrolled grade 2 or greater toxicity except alopecia related to any prior treatment (i.e. chemotherapy, targeted therapy, radiation or surgery) within 7 days prior to first dose unless approved by the Medical Monitor
2. Prolongation of QT/QTc interval
3. Women who are pregnant or nursing
4. Any known HIV infection or AIDS or any concurrent infection requiring IV antibiotics
5. Any chronic or concurrent acute liver disease, including viral hepatitis
6. Primary brain malignant tumors
7. Known metastases to the brain
8. Uncontrolled hypertension more than 150/100 mmHg
9. Concurrent participation in any other investigational study, unless non-interventional study and approved by Sponsor
10. Concurrent treatment with anticoagulation medication, except low molecular weight heparin, and approved by Sponsor
11. History of stroke, deep venous thrombosis (DVT), or transient ischemic attack (TIA), within 6 months prior to first dose
12. History of other cancer type, except for cutaneous basal cell or squamous cell carcinoma, or cervical in situ or very low/low risk prostate cancer, within the last 2 years prior to first dose.
13. Uncontrolled concurrent disease or illness including but not limited to:
a. symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia
b. unstable or untreated cardiac conditions or ejection fraction of less than 50% as determined by echocardiogram (ECHO) or multiple gated acquisition scan (MUGA)
c. diabetes mellitus
d. coagulation disorder
e. psychiatric illness that would limit compliance with study requirements, as determined by the Investigator
14. History of severe hypersensitivity reaction to taxanes.
15. For Phase 2a Stage 2: treatment with a taxane within 6 months of first dose; advanced prostate cancer patients must be taxane-naive
16. Peripheral neuropathy
17. Other severe, acute, or chronic medical or psychiatric condition or laboratory
abnormality that may increase the risk associated with study participation or study
drug administration or that may interfere with the interpretation of study results and,
in the judgment of the investigator, would make the patient inappropriate for the
study.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Dose-ranging.
Phase
Phase 1 / Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
Descriptive statistics including number, mean, median, standard deviation, minimum, and maximum values and PK parameters will be presented as appropriate for all cohorts treated. Listings of adverse events will be generated from this study. No formal sample size calculation is proposed as this study is not powered to demonstrate statistical significance.]

Recruitment
Recruitment status
Stopped early
Data analysis
Data analysis is complete
Reason for early stopping/withdrawal
Lack of funding/staff/facilities
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 3224 0
Liverpool Hospital - Liverpool
Recruitment hospital [2] 3225 0
Monash Medical Centre - Moorabbin campus - East Bentleigh
Recruitment hospital [3] 5591 0
Macquarie University Hospital - Macquarie Park
Recruitment postcode(s) [1] 9001 0
3165 - Bentleigh East
Recruitment postcode(s) [2] 9002 0
2170 - Liverpool
Recruitment postcode(s) [3] 13043 0
2109 - Macquarie University
Recruitment outside Australia
Country [1] 6499 0
United States of America
State/province [1] 6499 0

Funding & Sponsors
Funding source category [1] 290322 0
Commercial sector/Industry
Name [1] 290322 0
BlueLink Pharmaceuticals a subsidiary of NewLink Genetics
Address [1] 290322 0
2503 South Loop Drive, Ames, Iowa 50010,
Country [1] 290322 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
BlueLink Pharmaceuticals a subsidiary of NewLink Genetics
Address
2503 South Loop Drive, Ames, Iowa 50010
Country
United States of America
Secondary sponsor category [1] 289039 0
None
Name [1] 289039 0
Address [1] 289039 0
Country [1] 289039 0
Other collaborator category [1] 278254 0
Commercial sector/Industry
Name [1] 278254 0
Novotech (Australia) Pty Limited
Address [1] 278254 0
Level 3, 235 Pyrmont Street
Pyrmont NSW 2009
Country [1] 278254 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 292032 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 292032 0
246 Clayton Road, Clayton, VIC, 3168
Ethics committee country [1] 292032 0
Australia
Date submitted for ethics approval [1] 292032 0
18/06/2013
Approval date [1] 292032 0
12/02/2014
Ethics approval number [1] 292032 0
13218A

Summary
Brief summary
The purpose of this study is to determine the highest dose of a new drug known as CRLX301 that can safely be given to patients with advanced solid tumours.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above, and have a confirmed diagnosis of advanced solid tumor malignancy that is refractory (i.e. has not responded to treatment), or not a candidate for standard therapy.

Study details
All participants in this study will be treated with the study drug, CRLX301, which is administered intravenously (i.e. directly into the vein). CRLX301 is a combination of a chemotherapy drug called "docetaxel" and a polymer (group of the same molecules bound together). The docetaxel is attached to the polymer and forms into tiny beads called nanoparticles. The nanoparticles circulate in the blood stream and may eventually build up in tumours, allowing more of the chemotherapy drug, docetaxel, to get into tumour cells and kill them. The CRLX301 nanoparticle with docetaxel inside is larger than docetaxel alone. Therefore, it is hoped that less of it may enter normal healthy cells, so that normal healthy cells are not harmed.

The study has 2 parts. In the first part of the study (Part 1) participant groups will receive increasing doses of CRLX301 once every 3-weeks or once a week schedule if tolerated. If the dose causes significant side effects that are intolerable for patients, then no additional patients will be enrolled at a higher dose. In the second part of the study (Part 2), participants will receive the highest dose of CRLX301 which is not expected to cause significant side effects that would require stopping the dosing of study drug.

Participation in the study will require frequent clinic visits (at least weekly), to assess participants’ health and monitor side effects. Some visits may take up to 8 hours. Most other visits will last 2 - 3 hours depending on procedures required. These may be include: blood and urine sampling; physical examination; vital signs; medical history, performance status, concomitant medications and adverse events (AE) assessment; CT and bone scans; ECG; and tumour biopsy (second part of study only). After receiving CRLX301, additional blood samples will be required for some participants at 1 and 3 days; and 1 and possibly 2 weeks. Participants will continue to receive CRLX301 once every 3-weeks or weekly, unless they experience adverse events, in which case their CRLX301 may be delayed/given at a lower dose, or they may stop CRLX301. If participants experience unacceptable toxicity or disease progression, CRLX301 will be stopped and the participant will return for a safety follow up visit.

It is hoped that CRLX301 can be used to treat people with more chemotherapy in the tumour and with fewer effects on normal cells than with docetaxel alone.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 53130 0
Dr Benjamin Markman
Address 53130 0
Monash Medical Centre - Moorabbin Campus
865 Centre Road
East Bentleigh, VIC, 3165
Country 53130 0
Australia
Phone 53130 0
+ 61 3 9928 8111
Fax 53130 0
Email 53130 0
info@monashhealth.org
Contact person for public queries
Name 53131 0
Ms Lucy Tennant
Address 53131 0
BlueLink Pharmaceuticals a subsidiary of NewLink Genetics
2503 South Loop Drive, Ames, Iowa 50010

Country 53131 0
United States of America
Phone 53131 0
+ 1 5155982931
Fax 53131 0
Email 53131 0
ltennant@linkp.com
Contact person for scientific queries
Name 53132 0
Ms Lucy Tennant
Address 53132 0
BlueLink Pharmaceuticals a subsidiary of NewLink Genetics
2503 South Loop Drive, Ames, Iowa 50010

Country 53132 0
United States of America
Phone 53132 0
+ 1 5155982931
Fax 53132 0
Email 53132 0
ltennant@linkp.com

No information has been provided regarding IPD availability
Summary results
Have study results been published in a peer-reviewed journal?
Other publications
Have study results been made publicly available in another format?
Results – basic reporting
Results – plain English summary