Advanced Solid Tumors, HER2-negative Breast Cancer, Hormone Receptor Positive Breast Carcinoma, Metastatic Breast Cancer, Metastatic Colon Cancer, Rectal Cancer, Triple Negative Breast Cancer
Conditions
Keywords
VEGF, colorectal, breast
Brief summary
An open-label, dose escalation and expansion clinical trial to evaluate the safety, tolerability, and PK of fruquintinib in patients with advanced solid tumors, metastatic colorectal cancer and metastatic breast cancer.
Detailed description
The study was an open-label, dose escalation and expansion clinical trial to evaluate the safety, tolerability, and PK of fruquintinib in patients with advanced solid tumors. The study consisted of two phases: * A dose escalation phase - Two dose cohorts were evaluated including 3 mg orally QD 3 weeks on/1 week off and 5 mg orally QD 3 weeks on/1 week off. A 3+3 design was used for this portion of the study. * A dose expansion phase - Five cohorts were evaluated in Dose Expansion phase. Cohort A evaluated the MTD/RP2D in patients with advanced solid tumors of any type. Cohort B and Cohort C evaluated the MTD/RP2D in metastatic colorectal cancer patients. Cohort D and Cohort E evaluated the MTD/RP2D in metastatic breast cancer patients. Study was conducted at 9 sites in the United States.
Interventions
DRUGFruquintinib (HMPL-013)
Fruquintinib is a small molecule tyrosine kinase inhibitor (TKI) that targets VEGFR-1, -2, and -3, with a novel chemical structure which belongs to the quinazoline class.
Sponsors
Hutchison Medipharma Limited
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * Fully understand the study and voluntarily sign the ICF; * ≥18years of age; * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1; Dose Escalation Phase: • Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type (except squamous NSCLC) that has progressed on approved systemic therapy, and for whom no effective therapy or standard of care exists. This cohort is closed to enrollment. Dose Expansion Phase: * Cohort A: Histologically or cytologically documented, locally advanced or metastatic solid malignancy of any type (except squamous NSCLC), that has progressed on approved systemic therapy, and for whom no effective therapy or standard of care exists. This cohort is closed to enrollment. * Cohort B: Histologically or cytologically documented mCRC in patients that have progressed on, or had intolerable toxicity with at least 1 FDA-approved third-line systemic therapy (trifluridine/tipiracil or regorafenib). Patients must also have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy, and an anti-EGFR therapy for patients who had RAS wild-type tumors. This cohort is currently enrolling. * Cohort C: Histologically or cytologically documented adenocarcinoma of the colon or rectum. Patients must have progressed on, or had intolerable toxicity to, at least 2 prior regimens of standard chemotherapy, but must not have received prior TAS-102 or regorafenib. Prior therapy could have included adjuvant chemotherapy if a tumor had recurred within 6 months after the last administration of treatment. Patients must have been previously treated with fluoropyrimidine-, oxaliplatin-, and irinotecan-based chemotherapy, an anti-VEGF biological therapy and, if RAS wild-type, an anti-EGFR therapy * Cohort D only: Histologically- or cytologically-confirmed Her2-negative, hormone receptor positive (ER+ and/or PR+) breast cancer * Cohort E only: Histologically- or cytologically- confirmed triple negative breast cancer Key
Exclusion criteria
Patients will be excluded from the study, if any of the following criteria is met: * Severe anemia, neutropenia, thrombocytopenia * Moderate to severe renal or hepatic impairment * Uncontrolled hypertension * Risk of, or active hemorrhage: history or presence of active gastric/duodenal ulcer or ulcerative colitis, active hemorrhage of an unresected gastrointestinal tumor, history of perforation of fistulas; or any other condition that could possibly result in gastrointestinal tract hemorrhage or perforation within 6 months prior to screening; * History of a thromboembolic event (including deep vein thrombosis \[DVT\], pulmonary embolism, stroke and/or transient ischemic attack) within 6 months prior to screening; * Patients with squamous NSCLC; * Clinically significant cardiovascular disease, including but not limited to acute myocardial infarction or coronary artery bypass surgery within 6 months prior to enrollment, severe or unstable angina pectoris, New York Heart Association Class III/IV congestive heart failure, ventricular arrhythmias requiring treatment, or left ventricular ejection fraction (LVEF) \<50%; * Patients who have ever received a VEGFR inhibitor, except for patients with mCRC enrolled in the dose expansion phase; * Systemic anti-neoplastic therapies or any investigational therapy within 4 weeks prior to the first dose of study drug, including chemotherapy, radical radiotherapy, hormonotherapy, biotherapy and immunotherapy; * Systemic small molecule targeted therapies (e.g., tyrosine kinase inhibitors) within 5 half-lives or 4 weeks (whichever is shorter) prior to the first dose of study drug; * Palliative radiotherapy for bone metastasis/lesion within 2 weeks prior to the initiation of study drug; * Brachytherapy (ie, implantation of radioactive seeds) within 60 days prior to the first dose of study drug; * Known human immunodeficiency virus (HIV) infection; * Known clinically significant history of liver disease, including cirrhosis, current alcohol abuse or active viral hepatitis. For patients with evidence of chronic hepatitis B (HBV), the HBV viral load must be undetectable on suppressive therapy, if indicated. Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV who are currently on treatment, they are eligible if they have an undetectable HCV viral load; * Tumor invasion of a large vascular structure, eg, pulmonary artery, superior or inferior vena cava.; * Women who are pregnant or lactating; * 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; patients requiring steroids within 4 weeks prior to start of study treatment will be excluded; * No other malignancy, except for non-melanoma skin cancer, during the 5 years prior to screening; * Inability to take medication orally, dysphagia or an active gastric ulcer resulting from previous surgery (eg, gastric bypass) or a severe gastrointestinal disease, or any other condition that investigators believe may affect absorption of the investigational product; * Other disease, metabolic disorder, physical examination anomaly, abnormal laboratory result, or any other condition that investigators suspect may prohibit use of the investigational product, affect interpretation of study results, or put the patient at undue risk of harm based on the investigator's assessment; * Known hypersensitivity to fruquintinib or any of its excipients. * For Cohort C only: patients who have been previously treated with TAS-102 or regorafenib
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) | Cycle 1 (cycle length equal to [=] 28 days) | Dose-limiting toxicity was defined as: Any Grade 4 non-hematologic toxicity; Any Grade 3 non-hematologic toxicity related to study drug except for nausea/vomiting, diarrhea, constipation, hypertension, and electrolyte imbalances downgraded within 3-days with appropriate supportive treatment; Grade 4 neutropenia lasting \>3 days; Grade 3 febrile neutropenia (absolute neutrophil count \[ANC\] \<1.0\*10\^9 per liter \[/L\] with a single temperature of greater than (\>) 38.3 degree centigrade (°C) or a sustained temperature of greater than or equal to (\>=) 38°C for more than 1 hour); Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding; Dose interruption for \>14 days due to toxicity. |
| Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | From first dose of study drug up to 37 days after last dose of study drug (i.e., up to 29 months) | TEAEs were defined as AEs that started or worsened in severity on or after the first dose of study medication and no later than 37 days after the date of last study treatment. A serious adverse event (SAE) was any AE that had any of the following characteristics: Fatal (that was, the AE actually caused or led to death, except for deaths caused by the progress of disease); Life threatening (that was, AE, in view of the investigator, places participant at immediate risk of death); Required or prolonged inpatient hospitalization (excluding emergency or outpatient treatment); Resulted in persistent or significant disability/incapacity (that was, the AE resulted in substantial disruption of the participant's ability to conduct normal life functions). |
| Dose Expansion Phase: Progression Free Survival (PFS) Rate | From the first dose of study drug to disease progression, or death, whichever occurred first (i.e., up to 29 months) | PFS was defined as time from date of first dosing until date of an objective disease progression (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 or death due to any cause, whichever comes first. PFS was determined using all data until last evaluable visit prior to or on date of: (i) radiographic PD per RECIST v1.1; (ii) withdrawal of consent to obtain additional scans on study; or (iii) initiation of subsequent anticancer therapy other than study drugs, whichever was earlier. PFS rate was defined as probability of being disease progression free at selected timepoints such as 16 weeks and was calculated using Brookmeyer-Crowley method based on PFS events observed up to 29 months. PD:at least 20 percent (%) increase in sum of diameters of target lesions, taking as reference smallest sum on study, including baseline; an absolute increase of at least 5 millimeter (mm) in sum of diameters of target lesions; and appearance of one or more new lesions. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib | Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Day 14 of Cycle 1 (Cycle 1 length=28 days) | Tmin of fruquintinib was reported. |
| Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1, 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1 and 14 of Cycle 1 (Cycle 1 length=28 days) | AUC0-24 of fruquintinib was reported. |
| Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib | Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Day 14 of Cycle 1 (Cycle 1 length=28 days) | CL/Fss was calculated as Dose/AUC0-t. As planned, CL/Fss was assessed at Cycle 1 Days 14 and 21 after multiple dose administration in Dose Escalation Phase and Cohort A of Dose Expansion Phase; and at Cycle 1 Day 14 for Cohort B, C, D, E of Expansion Phase. |
| Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib | Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 14 and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Day 14 of Cycle 1 (Cycle 1 length=28 days) | Accumulation ratio based on Cmax for Cycle 1 Day 14 was calculated as Day 14 Cmax /Day 1 Cmax and for Cycle 1 Day 21 was calculated as Day 21 Cmax /Day 1 Cmax. Accumulation ratio based on Cmax of fruquintinib was reported. |
| Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib | Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 14 and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Day 14 of Cycle 1 (Cycle 1 length=28 days) | Accumulation ratio for Cycle 1 Day 14 was calculated as AUC0-24 at Day 14 divided by AUC0-24h at Day 1, and for Cycle 1 Day 21 was calculated as AUC0-24 at Day 21 divided by AUC0-24 at Day 1. Accumulation ratio based on AUC0-24 of fruquintinib was reported. |
| Dose Escalation and Expansion Phase: Objective Response Rate (ORR) | From the first dose of study drug until first documentation of best overall response (i.e., up to 29 months) | ORR was defined as the percentage of participants with objective complete response (CR) or partial response (PR) response per RECIST version 1.1. As per RECIST 1.1; CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. |
| Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1, 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1 and 14 of Cycle 1 (Cycle 1 length=28 days) | Cmax of fruquintinib was reported. |
| Dose Escalation and Expansion Phase: Duration of Response (DoR) | From the date of the first objective response (CR or PR) until the date of the documented disease progression or of death, whichever comes first (i.e., up to 29 months) | DoR was defined as the time (in months) from the date of the first objective response (CR or PR) until the date of the documented progression or of death, whichever comes first. DoR was only analyzed for participants whose best overall response (BOR) was either CR or PR. As per RECIST 1.1; CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this might include the baseline sum). DoR was calculated using the Kaplan-Meier method. |
| Dose Escalation and Expansion Phase: Progression Free Survival (PFS) | From date of first dose until the date of an objective disease progression or death due to any cause, whichever comes first (i.e., up to 29 months) | PFS was defined as the time (in months) from date of first dosing until the date of an objective disease progression as per RECIST version 1.1 or death due to any cause, whichever comes first. PFS was determined using all the assessment data up until the last evaluable visit prior to or on the date of (i) disease progression as defined by RECIST version 1.1 or death; or (ii) withdrawal of consent; or (iii) receiving subsequent anti-cancer therapy, whichever is earlier. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this might include the baseline sum). PFS was calculated using the Kaplan-Meier method. |
| Dose Escalation and Expansion Phase: Overall Survival (OS) | From first dose date to the date of death (due to any cause) (i.e., up to 29 months) | OS was defined as the time interval (in months) between the first dose date and the date of death (any cause). OS was calculated using the Kaplan-Meier method. |
| Dose Escalation and Expansion Phase: Percent Change From Baseline (PCFB) in Tumor Size | Baseline up to 29 months | Tumor size was estimated using data on sum of diameters of target lesion. Percentage change in tumor size from baseline was determined for participants with measurable disease at baseline and derived by the percentage change in the sum of the diameters of target lesions (TLs) compared to baseline. Baseline was defined as the last evaluable tumor assessment result obtained prior to the first administration of study medication. |
| Dose Expansion Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | From first dose of study drug up to 37 days after last dose of study drug (i.e., up to 29 months) | TEAEs were defined as AEs that started or worsened in severity on or after the first dose of study medication and no later than 37 days after the date of last study treatment. A SAE was any AE that had any of the following characteristics: Fatal (that was, the AE actually caused or led to death, except for deaths caused by the progress of disease); Life threatening (that was, AE, in view of the investigator, places participant at immediate risk of death); Required or prolonged inpatient hospitalization (excluding emergency or outpatient treatment); Resulted in persistent or significant disability/incapacity (that was, the AE resulted in substantial disruption of the participant's ability to conduct normal life functions). |
| Dose Escalation and Expansion Phase: Disease Control Rate (DCR) | From the first dose of study drug until first documentation of best overall response (i.e., up to 29 months) | DCR was defined as the percentage of participants with a best overall response (BOR) of confirmed CR, confirmed PR or stable disease (SD) (for 7 weeks) per RECIST version 1.1. As per RECIST 1.1; CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study \[this might include the baseline sum\]). |
| Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1, 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1 and 14 of Cycle 1 (Cycle 1 length=28 days) | Tmax of fruquintinib over a dosing intervals were reported. |
| Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib | Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Day 14 of Cycle 1 (Cycle 1 length=28 days) | Cmin of fruquintinib was reported. |
Countries
United States
Participant flow
Recruitment details
The study was conducted at 9 study sites in the United States.
Pre-assignment details
A total of 129 participants (14 in Dose Escalation Phase and 115 in Dose Expansion Phase) were treated in this study.
Participants by arm
| Arm | Count |
|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg Participants with advanced solid tumors of any type received fruquintinib 3 mg capsules (3 capsules, 1mg/capsule), once daily, 3 weeks on, 1 week off in each 28-day treatment cycle until disease progression, unacceptable toxicity, use of other antitumor treatment, withdrawal of consent, or discontinuation by Investigator, whichever occurred first. | 7 |
| Dose Escalation Phase: Fruquintinib 5 mg Participants with advanced solid tumors of any type received fruquintinib 5 mg capsule, once daily, 3 weeks on, 1 week off in each 28-day treatment cycle until disease progression, unacceptable toxicity, use of other antitumor treatment, withdrawal of consent, or discontinuation by Investigator, whichever occurred first. | 7 |
| Dose Expansion Phase, Cohort A: Fruquintinib 5 mg Participants with advanced solid tumors of any type received fruquintinib 5 mg capsule, once daily, 3 weeks on, 1 week off in each 28-day treatment cycle until disease progression, unacceptable toxicity, use of other antitumor treatment, withdrawal of consent, or discontinuation by Investigator, whichever occurred first. | 6 |
| Dose Expansion Phase, Cohort B: Fruquintinib 5 mg Participants with mCRC and prior treatment with trifluridine, tipiracil or regorafenib received fruquintinib 5 mg capsule, once daily, 3 weeks on, 1 week off in each 28-day treatment cycle until disease progression, unacceptable toxicity, use of other antitumor treatment, withdrawal of consent, or discontinuation by Investigator, whichever occurred first. | 41 |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg Participants with mCRC and no prior treatment with trifluridine, tipiracil or regorafenib received fruquintinib 5 mg capsule, once daily, 3 weeks on, 1 week off in each 28-day treatment cycle until disease progression, unacceptable toxicity, use of other antitumor treatment, withdrawal of consent, or discontinuation by Investigator, whichever occurred first. | 40 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg Participants with HR+, HER2-negative mBC received fruquintinib 5 mg capsule, once daily, 3 weeks on, 1 week off in each 28-day treatment cycle until disease progression, unacceptable toxicity, use of other antitumor treatment, withdrawal of consent, or discontinuation by Investigator, whichever occurred first. | 14 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg Participants with TNBC received fruquintinib 5 mg capsule, once daily, 3 weeks on, 1 week off in each 28-day treatment cycle until disease progression, unacceptable toxicity, use of other antitumor treatment, withdrawal of consent, or discontinuation by Investigator, whichever occurred first. | 14 |
| Total | 129 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 3 | 2 | 3 | 30 | 24 | 12 | 12 |
| Overall Study | Lost to Follow-up | 0 | 0 | 1 | 3 | 0 | 0 | 0 |
| Overall Study | Other | 2 | 3 | 2 | 0 | 1 | 1 | 1 |
| Overall Study | Patient withdrew consent and refused to provide follow-up information | 0 | 0 | 0 | 3 | 2 | 1 | 1 |
| Overall Study | Physician Decision | 0 | 2 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Progressive disease | 2 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation Phase: Fruquintinib 5 mg | Dose Expansion Phase, Cohort A: Fruquintinib 5 mg | Dose Expansion Phase, Cohort B: Fruquintinib 5 mg | Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 61.08 years STANDARD_DEVIATION 5.566 | 57.72 years STANDARD_DEVIATION 12.712 | 68.91 years STANDARD_DEVIATION 8.879 | 58.54 years STANDARD_DEVIATION 10.182 | 56.94 years STANDARD_DEVIATION 9.923 | 55.45 years STANDARD_DEVIATION 13.443 | 50.86 years STANDARD_DEVIATION 9.152 | 57.45 years STANDARD_DEVIATION 10.672 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 1 Participants | 0 Participants | 2 Participants | 1 Participants | 0 Participants | 1 Participants | 6 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 6 Participants | 6 Participants | 6 Participants | 38 Participants | 39 Participants | 13 Participants | 13 Participants | 121 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 2 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 0 Participants | 1 Participants | 5 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 0 Participants | 4 Participants | 4 Participants | 0 Participants | 4 Participants | 13 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 3 Participants | 0 Participants | 1 Participants | 0 Participants | 4 Participants |
| Race (NIH/OMB) White | 7 Participants | 6 Participants | 6 Participants | 33 Participants | 33 Participants | 13 Participants | 9 Participants | 107 Participants |
| Sex: Female, Male Female | 4 Participants | 6 Participants | 3 Participants | 21 Participants | 24 Participants | 14 Participants | 14 Participants | 86 Participants |
| Sex: Female, Male Male | 3 Participants | 1 Participants | 3 Participants | 20 Participants | 16 Participants | 0 Participants | 0 Participants | 43 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 3 / 7 | 2 / 7 | 3 / 6 | 30 / 41 | 25 / 40 | 12 / 14 | 12 / 14 |
| other Total, other adverse events | 7 / 7 | 7 / 7 | 6 / 6 | 41 / 41 | 39 / 40 | 14 / 14 | 14 / 14 |
| serious Total, serious adverse events | 3 / 7 | 2 / 7 | 4 / 6 | 19 / 41 | 14 / 40 | 2 / 14 | 4 / 14 |
Outcome results
Primary
Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs)
Dose-limiting toxicity was defined as: Any Grade 4 non-hematologic toxicity; Any Grade 3 non-hematologic toxicity related to study drug except for nausea/vomiting, diarrhea, constipation, hypertension, and electrolyte imbalances downgraded within 3-days with appropriate supportive treatment; Grade 4 neutropenia lasting \>3 days; Grade 3 febrile neutropenia (absolute neutrophil count \[ANC\] \<1.0\*10\^9 per liter \[/L\] with a single temperature of greater than (\>) 38.3 degree centigrade (°C) or a sustained temperature of greater than or equal to (\>=) 38°C for more than 1 hour); Grade 4 thrombocytopenia or Grade 3 thrombocytopenia associated with bleeding; Dose interruption for \>14 days due to toxicity.
Time frame: Cycle 1 (cycle length equal to [=] 28 days)
Population: The DLT evaluable set comprised all participants who were evaluable for DLT assessment. As planned, this outcome measure (OM) was assessed in Dose Escalation Phase only.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) | 1 Participants |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation Phase: Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
Primary
Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
TEAEs were defined as AEs that started or worsened in severity on or after the first dose of study medication and no later than 37 days after the date of last study treatment. A serious adverse event (SAE) was any AE that had any of the following characteristics: Fatal (that was, the AE actually caused or led to death, except for deaths caused by the progress of disease); Life threatening (that was, AE, in view of the investigator, places participant at immediate risk of death); Required or prolonged inpatient hospitalization (excluding emergency or outpatient treatment); Resulted in persistent or significant disability/incapacity (that was, the AE resulted in substantial disruption of the participant's ability to conduct normal life functions).
Time frame: From first dose of study drug up to 37 days after last dose of study drug (i.e., up to 29 months)
Population: The SAS included all participants who received at least 1 dose of the study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 7 Participants |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with serious TEAEs | 3 Participants |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with serious TEAEs | 2 Participants |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 7 Participants |
Primary
Dose Expansion Phase: Progression Free Survival (PFS) Rate
PFS was defined as time from date of first dosing until date of an objective disease progression (PD) as defined by Response Evaluation Criteria in Solid Tumors (RECIST) Version (v) 1.1 or death due to any cause, whichever comes first. PFS was determined using all data until last evaluable visit prior to or on date of: (i) radiographic PD per RECIST v1.1; (ii) withdrawal of consent to obtain additional scans on study; or (iii) initiation of subsequent anticancer therapy other than study drugs, whichever was earlier. PFS rate was defined as probability of being disease progression free at selected timepoints such as 16 weeks and was calculated using Brookmeyer-Crowley method based on PFS events observed up to 29 months. PD:at least 20 percent (%) increase in sum of diameters of target lesions, taking as reference smallest sum on study, including baseline; an absolute increase of at least 5 millimeter (mm) in sum of diameters of target lesions; and appearance of one or more new lesions.
Time frame: From the first dose of study drug to disease progression, or death, whichever occurred first (i.e., up to 29 months)
Population: The SAS included all participants who received at least 1 dose of the study drug.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Expansion Phase: Progression Free Survival (PFS) Rate | 53.33 percentage of participants |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Expansion Phase: Progression Free Survival (PFS) Rate | 61.04 percentage of participants |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Expansion Phase: Progression Free Survival (PFS) Rate | 55.64 percentage of participants |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Expansion Phase: Progression Free Survival (PFS) Rate | 29.30 percentage of participants |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Expansion Phase: Progression Free Survival (PFS) Rate | 38.46 percentage of participants |
Secondary
Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib
Accumulation ratio for Cycle 1 Day 14 was calculated as AUC0-24 at Day 14 divided by AUC0-24h at Day 1, and for Cycle 1 Day 21 was calculated as AUC0-24 at Day 21 divided by AUC0-24 at Day 1. Accumulation ratio based on AUC0-24 of fruquintinib was reported.
Time frame: Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 14 and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Day 14 of Cycle 1 (Cycle 1 length=28 days)
Population: PK evaluable population included all participants who received at least 1 dose of the study drug and had a sufficient PK profile to derive at least 1 PK parameter. Here, overall number of participants analyzed signifies participants who were evaluable for this OM. As per planned analysis, PK data were collected and reported for all cohorts at Cycle 1 Day 14; and for Dose Escalation Phase and Cohort A of Expansion Phase at Cycle 1 Day 21 only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib | Cycle 1 Day 14 | 4.24 ratio | Standard Deviation 1.21 |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib | Cycle 1 Day 21 | 4.36 ratio | Standard Deviation 1.53 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib | Cycle 1 Day 14 | 4.19 ratio | Standard Deviation 1.19 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib | Cycle 1 Day 21 | 3.90 ratio | Standard Deviation 0.964 |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib | Cycle 1 Day 21 | 4.43 ratio | — |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib | Cycle 1 Day 14 | 4.04 ratio | — |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib | Cycle 1 Day 14 | 3.87 ratio | Standard Deviation 1.22 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib | Cycle 1 Day 14 | 4.38 ratio | Standard Deviation 3.08 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib | Cycle 1 Day 14 | 3.73 ratio | Standard Deviation 1.51 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on AUC0-24 Hours of Fruquintinib | Cycle 1 Day 14 | 4.37 ratio | Standard Deviation 1.7 |
Secondary
Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib
Accumulation ratio based on Cmax for Cycle 1 Day 14 was calculated as Day 14 Cmax /Day 1 Cmax and for Cycle 1 Day 21 was calculated as Day 21 Cmax /Day 1 Cmax. Accumulation ratio based on Cmax of fruquintinib was reported.
Time frame: Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 14 and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Day 14 of Cycle 1 (Cycle 1 length=28 days)
Population: PK evaluable population: all participants who received at least 1 dose of study drug and had a sufficient PK profile to derive at least 1 PK parameter. Here, overall number of participants analyzed signifies participants evaluable for this OM; number analyzed signifies participants evaluable at specified timepoints. As per planned analysis, PK data were collected and reported for all cohorts at Cycle 1 Day 14; and for Dose Escalation Phase, Cohort A of Expansion Phase at Cycle 1 Day 21 only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib | Cycle 1 Day 14 | 4.06 ratio | Standard Deviation 1.42 |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib | Cycle 1 Day 21 | 4.22 ratio | Standard Deviation 1.45 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib | Cycle 1 Day 21 | 3.47 ratio | Standard Deviation 1.22 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib | Cycle 1 Day 14 | 3.66 ratio | Standard Deviation 1.42 |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib | Cycle 1 Day 14 | 3.57 ratio | Standard Deviation 0.232 |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib | Cycle 1 Day 21 | 3.40 ratio | — |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib | Cycle 1 Day 14 | 3.32 ratio | Standard Deviation 1.21 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib | Cycle 1 Day 14 | 3.44 ratio | Standard Deviation 1.36 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib | Cycle 1 Day 14 | 3.22 ratio | Standard Deviation 1.38 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Accumulation Ratio Based on Cmax of Fruquintinib | Cycle 1 Day 14 | 3.40 ratio | Standard Deviation 0.963 |
Secondary
Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib
CL/Fss was calculated as Dose/AUC0-t. As planned, CL/Fss was assessed at Cycle 1 Days 14 and 21 after multiple dose administration in Dose Escalation Phase and Cohort A of Dose Expansion Phase; and at Cycle 1 Day 14 for Cohort B, C, D, E of Expansion Phase.
Time frame: Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Day 14 of Cycle 1 (Cycle 1 length=28 days)
Population: PK evaluable population:all participants who received at least 1 dose of the study drug and had a sufficient PK profile to derive at least 1 PK parameter. Overall number of participants analyzed signifies participants evaluable for this OM; number analyzed signifies participants evaluable at specified timepoints. As per planned analysis, PK data were collected and reported for all cohorts at Cycle 1 Day 14; and for Dose Escalation Phase and Cohort A of Expansion Phase at Cycle 1 Day 21 only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib | Cycle 1 Day 14 | 14.4 milliliter per minute (mL/min) | Standard Deviation 2.9 |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib | Cycle 1 Day 21 | 14.1 milliliter per minute (mL/min) | Standard Deviation 3.07 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib | Cycle 1 Day 21 | 11.3 milliliter per minute (mL/min) | Standard Deviation 2.83 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib | Cycle 1 Day 14 | 11.1 milliliter per minute (mL/min) | Standard Deviation 4.04 |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib | Cycle 1 Day 21 | 17.5 milliliter per minute (mL/min) | — |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib | Cycle 1 Day 14 | 14.1 milliliter per minute (mL/min) | Standard Deviation 7.31 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib | Cycle 1 Day 14 | 16.3 milliliter per minute (mL/min) | Standard Deviation 5.16 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib | Cycle 1 Day 14 | 14.8 milliliter per minute (mL/min) | Standard Deviation 3.92 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib | Cycle 1 Day 14 | 14.7 milliliter per minute (mL/min) | Standard Deviation 7.18 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Apparent Clearance at Steady State (CL/Fss) of Fruquintinib | Cycle 1 Day 14 | 12.3 milliliter per minute (mL/min) | Standard Deviation 2.8 |
Secondary
Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib
AUC0-24 of fruquintinib was reported.
Time frame: Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1, 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1 and 14 of Cycle 1 (Cycle 1 length=28 days)
Population: PK evaluable population:all participants who received at least 1 dose of study drug and had a sufficient PK profile to derive at least 1 PK parameter. Overall number of participants analyzed signifies participants evaluable for this OM; number analyzed signifies participants evaluable at specified timepoints. As per planned analysis, PK data were collected and reported for all cohorts at Cycle 1 Days 1 and 14; and for Dose Escalation Phase, Cohort A of Expansion Phase at Cycle 1 Day 21 only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 14 | 3694 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 17.1 |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 1 | 912 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 21.5 |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 21 | 3731 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 22.5 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 1 | 2010 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 19.2 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 14 | 8249 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 35.2 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 21 | 7740 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 26.7 |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 21 | 4995 hour*nanogram per millimeter (h*ng/mL) | — |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 1 | 1340 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 25.6 |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 14 | 6507 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 53.7 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 14 | 5338 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 28.9 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 1 | 1384 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 39 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 1 | 1550 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 46.5 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 14 | 5833 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 27.3 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 14 | 6135 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 40.1 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 1 | 1821 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 31.5 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 1 | 1739 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 39.8 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Area Under the Plasma Concentration-time Curve From Time 0 to 24 Hours (AUC0-24) of Fruquintinib | Cycle 1 Day 14 | 6957 hour*nanogram per millimeter (h*ng/mL) | Geometric Coefficient of Variation 25.1 |
Secondary
Dose Escalation and Expansion Phase: Disease Control Rate (DCR)
DCR was defined as the percentage of participants with a best overall response (BOR) of confirmed CR, confirmed PR or stable disease (SD) (for 7 weeks) per RECIST version 1.1. As per RECIST 1.1; CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. SD was defined as neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study \[this might include the baseline sum\]).
Time frame: From the first dose of study drug until first documentation of best overall response (i.e., up to 29 months)
Population: The Efficacy Analysis Set included all participants who received at least 1 dose of fruquintinib, had a measurable lesion (target lesions \>=10 mm) at the baseline tumor assessment, and either: 1) had at least 1 postbaseline tumor assessment; or 2) did not have post-dose tumor assessment but had clinical progression as noted by the Investigator; or died due to disease progression before their first postbaseline tumor scan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Disease Control Rate (DCR) | 66.7 percentage of participants |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Disease Control Rate (DCR) | 71.4 percentage of participants |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Disease Control Rate (DCR) | 66.7 percentage of participants |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Disease Control Rate (DCR) | 68.3 percentage of participants |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Disease Control Rate (DCR) | 59.0 percentage of participants |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Disease Control Rate (DCR) | 60.0 percentage of participants |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Disease Control Rate (DCR) | 38.5 percentage of participants |
Secondary
Dose Escalation and Expansion Phase: Duration of Response (DoR)
DoR was defined as the time (in months) from the date of the first objective response (CR or PR) until the date of the documented progression or of death, whichever comes first. DoR was only analyzed for participants whose best overall response (BOR) was either CR or PR. As per RECIST 1.1; CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters. PD was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this might include the baseline sum). DoR was calculated using the Kaplan-Meier method.
Time frame: From the date of the first objective response (CR or PR) until the date of the documented disease progression or of death, whichever comes first (i.e., up to 29 months)
Population: Efficacy Analysis Set was used for analysis. Here, Overall number of participants analyzed signifies participants who had CR or PR; \& '0' in 'overall number of participants analyzed represents that DOR could only be analyzed in participants who achieved a response i.e., CR or PR. As no participant in the dose expansion cohorts A, D and E achieved any response, no DOR is available.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Duration of Response (DoR) | 7.56 months |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Duration of Response (DoR) | NA months |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Duration of Response (DoR) | 4.04 months |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Duration of Response (DoR) | NA months |
Secondary
Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib
Cmax of fruquintinib was reported.
Time frame: Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1, 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1 and 14 of Cycle 1 (Cycle 1 length=28 days)
Population: Pharmacokinetic (PK) evaluable population included all participants who received at least 1 dose of the study drug and had a sufficient PK profile to derive at least 1 PK parameter. Here, number analyzed signifies participants who were evaluable at specified timepoints. As per planned analysis, PK data were collected and reported for all cohorts at Cycle 1 Days 1 and 14; and for the Dose Escalation Phase and Cohort A of Expansion Phase at Cycle 1 Day 21 only.
| Arm | Measure | Group | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 1 | 52.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 24.2 |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 14 | 198 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 9.8 |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 21 | 205 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 12.8 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 14 | 403 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 33.7 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 1 | 114 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 27.5 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 21 | 390 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 19.1 |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 21 | 238 nanogram per milliliter (ng/mL) | — |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 1 | 96.0 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 23 |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 14 | 336 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 50.9 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 1 | 85.2 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 32.1 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 14 | 271 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 26.5 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 14 | 293 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 27.1 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 1 | 89.0 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 43.2 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 1 | 104 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 37 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 14 | 331 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 36.1 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 1 | 105 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 36.5 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Maximum Observed Plasma Concentration (Cmax) of Fruquintinib | Cycle 1 Day 14 | 352 nanogram per milliliter (ng/mL) | Geometric Coefficient of Variation 23.4 |
Secondary
Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib
Cmin of fruquintinib was reported.
Time frame: Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Day 14 of Cycle 1 (Cycle 1 length=28 days)
Population: PK evaluable population: all participants who received at least 1 dose of study drug and had a sufficient PK profile to derive at least 1 PK parameter. Overall number of participants analyzed signifies participants evaluable for this OM; number analyzed signifies participants evaluable at specified timepoints. As per planned analysis, PK data were collected and reported for all cohorts at Cycle 1 Day 14; and for Dose Escalation Phase and Cohort A of Expansion Phase at Cycle 1 Day 21 only.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib | Cycle 1 Day 21 | 140 ng/mL | Standard Deviation 27 |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib | Cycle 1 Day 14 | 138 ng/mL | Standard Deviation 28.3 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib | Cycle 1 Day 21 | 283 ng/mL | Standard Deviation 81 |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib | Cycle 1 Day 14 | 281 ng/mL | Standard Deviation 101 |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib | Cycle 1 Day 21 | 182 ng/mL | — |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib | Cycle 1 Day 14 | 251 ng/mL | Standard Deviation 114 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib | Cycle 1 Day 14 | 193 ng/mL | Standard Deviation 57.3 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib | Cycle 1 Day 14 | 204 ng/mL | Standard Deviation 63.2 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib | Cycle 1 Day 14 | 227 ng/mL | Standard Deviation 98.4 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Minimum Observed Plasma Concentration (Cmin) of Fruquintinib | Cycle 1 Day 14 | 249 ng/mL | Standard Deviation 72.1 |
Secondary
Dose Escalation and Expansion Phase: Objective Response Rate (ORR)
ORR was defined as the percentage of participants with objective complete response (CR) or partial response (PR) response per RECIST version 1.1. As per RECIST 1.1; CR was defined as disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to \<10 mm. PR was defined at least a 30 percent (%) decrease in the sum of diameters of target lesions, taking as reference the baseline sum of diameters.
Time frame: From the first dose of study drug until first documentation of best overall response (i.e., up to 29 months)
Population: The Efficacy Analysis Set included all participants who received at least 1 dose of fruquintinib, had a measurable lesion (target lesions \>=10 mm) at the baseline tumor assessment, and either: 1) had at least 1 postbaseline tumor assessment; or 2) did not have post-dose tumor assessment but had clinical progression as noted by the Investigator; or died due to disease progression before their first postbaseline tumor scan.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Objective Response Rate (ORR) | 16.7 percentage of participants |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Objective Response Rate (ORR) | 14.3 percentage of participants |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Objective Response Rate (ORR) | 0.0 percentage of participants |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Objective Response Rate (ORR) | 2.4 percentage of participants |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Objective Response Rate (ORR) | 5.1 percentage of participants |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Objective Response Rate (ORR) | 0.0 percentage of participants |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Objective Response Rate (ORR) | 0.0 percentage of participants |
Secondary
Dose Escalation and Expansion Phase: Overall Survival (OS)
OS was defined as the time interval (in months) between the first dose date and the date of death (any cause). OS was calculated using the Kaplan-Meier method.
Time frame: From first dose date to the date of death (due to any cause) (i.e., up to 29 months)
Population: The SAS included all participants who received at least 1 dose of the study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Overall Survival (OS) | 22.70 months |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Overall Survival (OS) | 19.58 months |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Overall Survival (OS) | 6.03 months |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Overall Survival (OS) | 8.71 months |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Overall Survival (OS) | 10.64 months |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Overall Survival (OS) | 12.06 months |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Overall Survival (OS) | 8.74 months |
Secondary
Dose Escalation and Expansion Phase: Percent Change From Baseline (PCFB) in Tumor Size
Tumor size was estimated using data on sum of diameters of target lesion. Percentage change in tumor size from baseline was determined for participants with measurable disease at baseline and derived by the percentage change in the sum of the diameters of target lesions (TLs) compared to baseline. Baseline was defined as the last evaluable tumor assessment result obtained prior to the first administration of study medication.
Time frame: Baseline up to 29 months
Population: Efficacy Analysis Set: all participants who received at least 1 dose of fruquintinib, had a measurable lesion (target lesions \>=10 mm) at baseline tumor assessment and either: 1) had at least 1 postbaseline tumor assessment; or 2) did not have post-dose tumor assessment but had clinical progression as noted by Investigator; or died due to disease progression before first postbaseline tumor scan. Overall number of participants analyzed signifies participants evaluable for this OM.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Percent Change From Baseline (PCFB) in Tumor Size | 5.41 percent change | — |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Percent Change From Baseline (PCFB) in Tumor Size | -20.70 percent change | Standard Deviation 16.485 |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Percent Change From Baseline (PCFB) in Tumor Size | -12.92 percent change | Standard Deviation 25.919 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Percent Change From Baseline (PCFB) in Tumor Size | 7.40 percent change | Standard Deviation 23.713 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Percent Change From Baseline (PCFB) in Tumor Size | 19.23 percent change | Standard Deviation 20.808 |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Percent Change From Baseline (PCFB) in Tumor Size | -8.07 percent change | Standard Deviation 8.574 |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Percent Change From Baseline (PCFB) in Tumor Size | 9.82 percent change | Standard Deviation 16.824 |
Secondary
Dose Escalation and Expansion Phase: Progression Free Survival (PFS)
PFS was defined as the time (in months) from date of first dosing until the date of an objective disease progression as per RECIST version 1.1 or death due to any cause, whichever comes first. PFS was determined using all the assessment data up until the last evaluable visit prior to or on the date of (i) disease progression as defined by RECIST version 1.1 or death; or (ii) withdrawal of consent; or (iii) receiving subsequent anti-cancer therapy, whichever is earlier. Disease progression was defined as at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study (this might include the baseline sum). PFS was calculated using the Kaplan-Meier method.
Time frame: From date of first dose until the date of an objective disease progression or death due to any cause, whichever comes first (i.e., up to 29 months)
Population: The SAS included all participants who received at least 1 dose of the study drug.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Progression Free Survival (PFS) | 6.90 months |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Progression Free Survival (PFS) | NA months |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Progression Free Survival (PFS) | 5.49 months |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Progression Free Survival (PFS) | 4.67 months |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Progression Free Survival (PFS) | 3.75 months |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Progression Free Survival (PFS) | 2.43 months |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Progression Free Survival (PFS) | 1.87 months |
Secondary
Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib
Tmax of fruquintinib over a dosing intervals were reported.
Time frame: Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1, 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 1 and 14 of Cycle 1 (Cycle 1 length=28 days)
Population: PK evaluable population included all participants who received at least 1 dose of the study drug and had a sufficient PK profile to derive at least 1 PK parameter. Here, number analyzed signifies participants who were evaluable at specified timepoints. As per planned analysis, PK data were collected and reported for all cohorts at Cycle 1 Days 1 and 14; and for the Dose Escalation Phase and Cohort A of Expansion Phase at Cycle 1 Day 21 only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 1 | 2.07 hours |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 21 | 1.83 hours |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 14 | 1.03 hours |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 1 | 1.95 hours |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 14 | 2.00 hours |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 21 | 2.00 hours |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 14 | 1.52 hours |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 1 | 1.96 hours |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 21 | 1.00 hours |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 14 | 2.03 hours |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 1 | 2.25 hours |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 14 | 2.00 hours |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 1 | 2.04 hours |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 1 | 2.00 hours |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 14 | 1.86 hours |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 14 | 1.84 hours |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Maximum Observed Plasma Concentration (Tmax) of Fruquintinib | Cycle 1 Day 1 | 2.01 hours |
Secondary
Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib
Tmin of fruquintinib was reported.
Time frame: Dose Escalation and Cohort A of Expansion Phases: Predose, 1, 2, 4, 8, 24 hours post-dose on Days 14, and 21 of Cycle 1; Cohorts B, C, D, E of Expansion Phase: Predose, 1, 2, 4, 8, 24 hours post-dose on Day 14 of Cycle 1 (Cycle 1 length=28 days)
Population: PK evaluable population: all participants who received at least 1 dose of study drug and had a sufficient PK profile to derive at least 1 PK parameter. Overall number of participants analyzed signifies participants evaluable for this OM; number analyzed signifies participants evaluable at specified timepoints. As per planned analysis, PK data were collected and reported for all cohorts at Cycle 1 Day 14; and for Dose Escalation Phase and Cohort A of Expansion Phase at Cycle 1 Day 21 only.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib | Cycle 1 Day 21 | 7.00 hours |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib | Cycle 1 Day 14 | 0.00 hours |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib | Cycle 1 Day 21 | 3.54 hours |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib | Cycle 1 Day 14 | 0.508 hours |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib | Cycle 1 Day 21 | 7.00 hours |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib | Cycle 1 Day 14 | 3.57 hours |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib | Cycle 1 Day 14 | 0.00 hours |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib | Cycle 1 Day 14 | 0.00 hours |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib | Cycle 1 Day 14 | 0.00 hours |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Escalation and Expansion Phase: Time to Reach Minimum Observed Plasma Concentration (Tmin) of Fruquintinib | Cycle 1 Day 14 | 0.458 hours |
Secondary
Dose Expansion Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs
TEAEs were defined as AEs that started or worsened in severity on or after the first dose of study medication and no later than 37 days after the date of last study treatment. A SAE was any AE that had any of the following characteristics: Fatal (that was, the AE actually caused or led to death, except for deaths caused by the progress of disease); Life threatening (that was, AE, in view of the investigator, places participant at immediate risk of death); Required or prolonged inpatient hospitalization (excluding emergency or outpatient treatment); Resulted in persistent or significant disability/incapacity (that was, the AE resulted in substantial disruption of the participant's ability to conduct normal life functions).
Time frame: From first dose of study drug up to 37 days after last dose of study drug (i.e., up to 29 months)
Population: The SAS included all participants who received at least 1 dose of the study drug.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Expansion Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 6 Participants |
| Dose Escalation Phase: Fruquintinib 3 mg | Dose Expansion Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with serious TEAEs | 4 Participants |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Expansion Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 41 Participants |
| Dose Escalation Phase: Fruquintinib 5 mg | Dose Expansion Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with serious TEAEs | 19 Participants |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Expansion Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 39 Participants |
| Dose Expansion Phase, Cohort C: Fruquintinib 5 mg | Dose Expansion Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with serious TEAEs | 14 Participants |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Expansion Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with serious TEAEs | 2 Participants |
| Dose Expansion Phase, Cohort D: Fruquintinib 5 mg | Dose Expansion Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 14 Participants |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Expansion Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with TEAEs | 14 Participants |
| Dose Expansion Phase, Cohort E: Fruquintinib 5 mg | Dose Expansion Phase: Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious TEAEs | Participants with serious TEAEs | 4 Participants |