| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Refractory metastatic colorectal cancer |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052358 |
| E.1.2 | Term | Colorectal cancer metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10052362 |
| E.1.2 | Term | Metastatic colorectal cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To evaluate the overall survival of fruquintinib plus BSC compared to placebo plus BSC in subjects with refractory mCRC. |
|
| E.2.2 | Secondary objectives of the trial |
• To evaluate progression-free survival (PFS) of fruquintinib plus BSC compared to placebo plus BSC
• To evaluate the objective response rate (ORR), disease control rate (DCR), and duration of response (DoR)
• To assess the safety and tolerability of fruquintinib plus BSC compared to placebo plus BSC
• To characterize the PK exposure of fruquintinib and metabolite M11 in subjects with refractory mCRC
• To evaluate the effect of fruquintinib on cardiac repolarization, as detected by changes in electrocardiogram (ECG) QTc intervals, and the potential relationship with fruquintinib and M11 plasma concentrations
• To evaluate the relationship between fruquintinib exposure and endpoints for efficacy and safety
• To evaluate quality of life (QoL) as assessed by using QLQ-C30: cancer-specific; and EQ-5D-5L questionnaires
• To assess resource utilization
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Provide written informed consent;
2. Age ≥18 years;
3. Histologically and/or cytologically documented metastatic colorectal
adenocarcinoma. RAS, BRAF, and microsatellite instability
(MSI)/mismatch repair (MMR) status for each subject must be
documented, according to country level guidelines;
4. Subjects must have progressed on or been intolerant to treatment
with either trifluridine/tipiracil (TAS-102) or regorafenib. Subjects are
considered intolerant to TAS-102 or regorafenib if they have received at
least 1 dose of either agent and were discontinued from therapy for
reasons other than disease progression. Subjects who have been treated
with both TAS-102 and regorafenib are permitted. Subjects must also
have been previously treated with standard approved therapies:
fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an
anti-VEGF biological therapy (eg, bevacizumab, aflibercept,
ramucirumab) [Please note that regorafenib is NOT an anti-VEGF
biologic], and, if RAS wildtype, an anti-EGFR therapy (eg, cetuximab,
panitumumab);
5. Subjects with microsatellite-high (MSI-H) or mismatch repair deficient
(dMMR) tumors must have been treated with immune checkpoint
inhibitors if approved and available in the subject's country unless the
subject is ineligible for treatment with a checkpoint inhibitor;
6. Subjects who received oxaliplatin in the adjuvant setting and
developed metastatic disease during or within 6 months of completing
adjuvant therapy are considered eligible without receiving oxaliplatin in
the metastatic setting. Subjects who developed metastatic disease more
than 6 months after completion of oxaliplatin-containing adjuvant
treatment must be treated with oxaliplatin-based therapy in the
metastatic setting to be eligible;
7. Body weight ≥ 40kg;
8. Eastern Cooperative Oncology Group (ECOG) performance status of 0
to 1;
9. Have measurable disease according to RECIST Version1.1 (RECIST
v1.1), assessed locally. Tumors that were treated with radiotherapy are
not measurable per RECIST v1.1, unless there has been documented
progression of those lesions;
10. Expected survival >12 weeks;
11. For female subjects of childbearing potential and male subjects with
partners of childbearing potential, agreement to use a highly effective
form(s) of contraception, that results in a low failure rate (<1% per
year) when used consistently and correctly, starting during the
screening period, continuing throughout the entire study period, and for
90 days after taking the last dose of study drug. Such methods include:
oral hormonal contraception (combined estrogen/ progestogen, or
progestogen-only) associated with inhibition of ovulation, intrauterine
device (IUD), intrauterine hormone-releasing system (IUS), bilateral
tubal ligation, vasectomized partner, or true sexual abstinence in line
with the preferred and usual lifestyle of the subject. Highly effective
contraception should always be combined with an additional barrier
method (eg, diaphragm, with a spermicide). The same criteria are
applicable to male subjects involved in this clinical trial if they have a
partner of childbirth potential, and male subjects must always use a
condom;
12. Subjects with BRAF-mutant tumors must have been treated with a
BRAF inhibitor if approved and available in the subject's country unless
the subject is ineligible for treatment with a BRAF inhibitor; |
|
| E.4 | Principal exclusion criteria |
1. Absolute neutrophil count (ANC) <1.5×109/L, platelet count <100 × 109/L, or hemoglobin <9.0 g/dL. Blood transfusion within 1 week prior to enrollment for the purpose of increasing the likelihood of eligibility is not allowed;
2. Serum total bilirubin >1.5 × the upper limit of normal (ULN). Subjects with previously documented Gilbert syndrome and bilirubin <2 X ULN are eligible;
3. ALT or AST >2.5 × ULN in subjects without hepatic metastases; ALT or AST >5 ×ULN in subjects with hepatic metastases;
4. Serum creatinine >1.5 × ULN or creatinine clearance <60 mL/min. Creatinine clearance can either be measured in a 24-hour urine collection or estimated by the Cockcroft-Gault equation;
5. Urine dipstick or urinalysis with protein ≥2+ or 24-hour urine protein ≥1.0 g/24-h. Subjects with 1+ proteinuria must undergo a 24-hour urine collection to assess urine protein level.
6. Uncontrolled hypertension, defined as: systolic blood pressure ≥140 mmHg and/or diastolic blood pressure ≥90 mm Hg despite optimal medical management. The subject must have blood pressures below both limits. Repeated assessments are permitted;
7. International Normalized Ratio (INR) >1.5 x ULN or activated partial thromboplastin time (aPTT) >1.5 × ULN, unless the subject is currently receiving or intended to receive anticoagulants for prophylactic purposes;
8. History of, or active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation or fistulas; or any other condition that could, in the investigator's judgment, result in gastrointestinal hemorrhage or perforation; within the 6 months prior to screening;
9. History or presence of hemorrhage from any other site within 2 months prior to screening;
10. History of a thromboembolic event within 6 months prior to screening;
11. Stroke and/or transient ischemic attack within 12 months prior to screening;
12. Clinically significant cardiovascular disease as described in the protocol.
13. Corrected QT interval using the Fridericia method (QTcF) >480 msec or any factors that increase the risk of QTc prolongation or risk of arrhythmic events as described in the protocol.
14. Concomitant medications with a known risk of causing QT prolongation and/or Torsades de Pointes;
15. Systemic anti-neoplastic therapies (except for those described in Exclusion Criterion 18) or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy;
16. Systemic small molecule targeted therapies within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug;
17. Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug;
18. Brachytherapy within 60 days prior to the first dose of study drug;
19. Use of strong inducers or inhibitors of CYP3A4 within 2 weeks (or 5 half-lives, whichever is longer) before the first dose of study drug;
20. Surgery or invasive procedure within 60 days prior to the first dose of study drug or unhealed surgical incision;
21. Any unresolved toxicities from a previous antitumor treatment as described in the protocol.
22. Known HIV infection;
23. Known history of active viral hepatitis;
24. Clinically uncontrolled active infection requiring IV antibiotics;
25. Tumor invasion of a large vascular structure;
26. Women who are pregnant or lactating;
27. Brain metastases and/or spinal cord compression untreated with surgery and/or radiotherapy, and without clinical imaging evidence of stable disease for 14 days or longer; subjects requiring steroids within 4 weeks prior to start of study treatment are excluded;
28. Other malignancy, except for non-melanoma skin cancer, in situ cervical ca or bladder ca (Tis and T1) that have been adequately treated during the 5 years prior to screening;
29. Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product;
30. Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition (eg, current alcohol or drug abuse) that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the subject at undue risk of harm based on the investigator's assessment;
31. Known hypersensitivity to fruquintinib or any of its (or placebo) inactive ingredients including the azo dyes Tartrazine - FD&C Yellow 5 and Sunset yellow FCF - FD&C Yellow 6;
32. Subjects who have received prior fruquintinib;
33. Live vaccine ≤28 days before the first dose of study drug(s).
Seasonal vaccines for influenza are generally inactivated vaccines and are allowed. Intranasal vaccines are live vaccines and are not allowed. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| The primary endpoint of the study is overall survival, defined as the time (months) from date of randomization to death from any cause. Subjects without report of death at the time of analysis will be censored at the date last known alive. |
|
| E.5.2 | Secondary end point(s) |
- Progression-free survival (PFS)
- Objective response rate (ORR)
- Disease control rate (DCR)
- Duration of response (DoR)
- Safety including TEAEs, SAEs, deaths, ECG’s, and clinical laboratory abnormalities;
- Observed plasma concentrations, estimated population PK and exposure parameters of fruquintinib and M11;
- QTc interval and plasma concentrations of fruquintinib and M11 at specified time points;
- Parameters describing exposure-response with efficacy (eg, OS) and safety (eg, AEs) endpoints;
- Changes in health status (QLQ-C30: cancerspecific; and EQ-5D-5L);
- Resource utilization including all concomitant medications, days in hospital. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- PFS is defined as the time (months) from randomization until the first radiographic documentation of objective progression as assessed by investigator or death from any cause.
- Objective response rate is defined as the proportion of subjects achieving a best overall response of confirmed complete response (CR) or partial response (PR), per RECIST v1.1, as determined by the investigator.
- Disease control rate is defined as proportion of subjects achieving a best overall response of confirmed CR, PR, or SD, per RECIST v1.1, as determined by the investigator.
- Duration of response is defined as the time (months) from the first occurrence of PR or CR, whichever comes first, until the date of radiographic PD or death.
Refer to the protocol for additional timepoints. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 15 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 103 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Japan |
| United States |
| Austria |
| Belgium |
| Czechia |
| Estonia |
| France |
| Germany |
| Hungary |
| Italy |
| Poland |
| Spain |
| United Kingdom |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 10 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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