Metastatic Colorectal Cancer, KRAS Gene Mutation
Conditions
Keywords
KRAS mutation, PCM-075, Onvansertib, FOLFIRI, Irinotecan, 5-Fluorouracil, Leucovorin, Avastin, Bevacizumab, PLK1, PLK Inhibitor
Brief summary
The purpose of the Phase 1b/2 study is to determine the safety and efficacy of Onvansertib, administered orally, daily on Day 1-5 and Day 15-19 of each 28-day cycle, in combination with FOLFIRI + Bevacizumab, as second-line treatment in adult participants who have metastatic colorectal cancer with a KRAS mutation. Participants must have histologically confirmed metastatic and unresectable disease, and previously failed treatment or be intolerant to fluoropyrimidine and oxaliplatin with or without bevacizumab.
Interventions
DRUGOnvansertib
Onvansertib orally.
BIOLOGICALBevacizumab
Bevacizumab intravenously.
DRUGFOLFIRI
FOLFIRI intravenously.
Sponsors
Cardiff Oncology
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Histologically confirmed metastatic and unresectable colorectal cancer (CRC). * Documentation of a KRAS mutation in exon 2, 3 or 4 in primary tumor or metastasis, assessed by a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory. Participants with concomitant KRAS and BRAF-V600 mutations are excluded from this study. Participants with Microsatellite Instability High/Deficient Mismatch Repair (MSI-H/ddMMR) are also ineligible for enrollment in this study. * Formalin-fixed, paraffin-embedded (FFPE) tumor tissue must be available for submission to a central laboratory in order for a participant to be eligible. If no archival tissue biopsy is available the participant must have a biopsy obtained at screening. * Age ≥ 18 years. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. * Signed informed consent for participation in the study. * Participant is not receiving any other standard-of-care or experimental cancer therapy. Participants participating in non-interventional surveys or observational studies are allowed. * Has failed treatment or is intolerant of fluoropyrimidine and oxaliplatin with or without bevacizumab. 1. Participants must have had systemic therapy within 180 days of the screening visit, but can have no anti-cancer therapy within 28 days of the planned first day of treatment on study. 2. Participants must have received oxaliplatin based chemotherapy with or without bevacizumab (\>6 weeks in duration). Participants who received maintenance therapy with fluoropyrimidines are eligible with or without re-challenge with oxaliplatin in combination with fluoropyrimidines. 3. Participants who received oxaliplatin/fluoropyrimidine-based neoadjuvant or adjuvant therapy and have disease recurrence or progression \> 6 months from their last dose of neoadjuvant or adjuvant treatment (or \> 6 months from surgery if no adjuvant therapy was administered) will be required to have received fluoropyrimidine/oxaliplatin-based therapy with or without bevacizumab as first-line treatment for metastatic disease. 4. Participants must not have received prior irinotecan. 5. For participants with rectal cancer, sequential neoadjuvant and adjuvant therapy will count as a single systemic regimen for advanced disease. 6. Participants who discontinued first-line therapy because of toxicity are eligible for as long as progression occurred \< 6 months after the last dose of first-line therapy. * Chemotherapy regimen of irinotecan, fluorouracil \[5-FU\], and leucovorin (FOLFIRI) therapy is appropriate for the participant as determined by the Investigator. * For a woman of child-bearing potential (WOCBP) or a male with a female partner who is a WOCBP: must have a negative serum or urine pregnancy test within 5 days prior to enrollment. WOCBP include any female who has experienced menarche and who has not undergone successful surgical sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is not postmenopausal (defined as amenorrhea \> 12 consecutive months); or women on hormone replacement therapy (HRT) with documented serum follicle stimulating hormone (FSH) level \> 35 mIU/mL. Even women who are using oral, implanted or injectable contraceptive hormones or mechanical products such as an intrauterine device (IUD) or barrier methods (diaphragm, condoms, spermicides) to prevent pregnancy or practicing abstinence or where partner is sterile (e.g., vasectomy), should be considered to be of child-bearing potential. * Imaging computed tomography (CT)/ magnetic resonance imaging (MRI) of chest/abdomen/pelvis or other scans as necessary to document all sites of disease performed within 21 days prior to enrollment. Only participant with measurable disease as defined per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1) are eligible for enrollment. CT is the preferred imaging modality, but MRI is also accepted. * Must have acceptable organ function. * Participant must consent to provision of, and Investigator(s) must confirm access to and agree to submit a representative, formalin fixed, paraffin block of tumor tissue to be used for correlative marker assays. Submission of the tissue does not have to occur prior to enrollment. * Signed informed consent to provide blood sample(s) for specific correlative assays.
Exclusion criteria
* Concomitant KRAS and BRAF-V600 mutations or MSI-H/dMMR * Anti-cancer chemotherapy or biologic therapy administered within 28 days prior to the first dose of study drug. The exception is a single dose of radiation up to 8 Gray (equal to 800 RAD) with palliative intent for pain control up to 14 days before randomization. * More than one prior chemotherapy regimen administered in the metastatic setting. * Major surgery within 6 weeks prior to enrollment. * Untreated or symptomatic brain metastasis. * Women who are pregnant or breastfeeding. * Gastrointestinal (GI) disorder(s) that, in the opinion of the Investigator, would significantly impede the absorption of an oral agent (e.g., intestinal occlusion, active Crohn's disease, ulcerative colitis, extensive gastric and small intestine resection). * Unable or unwilling to swallow study drug. * Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, clinically significant non-healing or healing wounds, symptomatic congestive heart failure (CHF) Class II or higher according to the New York Heart Association (NYHA) Functional Classification, unstable angina pectoris, clinically significant cardiac arrhythmia, significant pulmonary disease (shortness of breath at rest or mild exertion), uncontrolled infection or psychiatric illness/social situations that would limit compliance with study requirements. 1. Known active infection with Human Immunodeficiency Virus (HIV), with measurable viral titer, and/or active infection with hepatitis B or C (participants who have had a hepatitis B virus \[HBV\] immunization are eligible). 2. Known active infection with SARS-CoV-2. 3. Clinically significant ascites or pleural effusions. * Known hypersensitivity to 5-FU/leucovorin. * Known hypersensitivity to irinotecan. * Abnormal glucuronidation of bilirubin: known Gilbert's syndrome. * Participants with a history of other malignancies except: adequately treated non-melanoma skin cancer, curatively treated in-situ cancer of the cervix or prostate, or other solid tumors curatively treated with no evidence of disease for \> 2 years. * Any active disease condition that would render the protocol treatment dangerous or impair the ability of the participant to receive study drug. * Planned concomitant use of medications known to prolong the QT/QTc interval according to institutional guidelines. * Presence of risk factors for torsade de pointes, including family history of Long QT Syndrome or uncorrected hypokalemia. * The following are
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) | Up to Day 28 | DLTs were defined as a Grade 4 hematologic adverse events (AEs), Grade ≥ 3 non-hematologic AEs that were considered related to the study drug and that did not resolve within 14 days following presentation with standard management and care, Grade ≥ 3 thrombocytopenia with bleeding, neutropenic fever, any death not clearly due to the underlying disease or extraneous causes, or any change in liver function that met Hy's Law criteria of a DLT. |
| Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Up to a maximum of 81 weeks | AEs were defined as any untoward medical occurrence associated with the use of a drug in humans. TEAEs are defined as any AE that started on or after the first day of study treatment and within 30 days of the last administration of study treatment, or that worsened on or after the first day of study treatment. AE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 on a scale from Grade 1 (mild) to Grade 5 (death). An AE was considered serious if it resulted in death, life-threatening AE, hospitalization or prolongation of hospitalization, persistent or significant incapacity, or congenital anomaly/birth defect. The Investigator determined relatedness to the use of onvansertib. Clinically significant changes in vital signs, laboratory parameters, electrocardiograms, physical examinations, weight, and Eastern Cooperative Oncology Group (ECOG) performance status were reported as AEs. |
| All-Treated Analysis Set: Objective Response Rate (ORR) | Up to a maximum of 131 weeks | ORR was defined as the percentage of participants documented to have a confirmed complete response (CR) or partial response (PR) using the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1). Two-sided 95% confidence interval (CI) was calculated using the exact binomial Clopper-Pearson method. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| All-Treated Analysis Set: Duration of Response (DoR) | Up to a maximum of 131 weeks | DoR was calculated as the (date of first documented tumor progression or death due to any cause minus date of first documentation of a subsequently confirmed objective response plus 1)/30.4375. Participants who did not have an observed documented PD or death from any cause were censored at the latest tumor response assessment date. |
| All-Treated Analysis Set: Overall Survival (OS) | Up to a maximum of 131 weeks | OS was defined as the time in months from the date of first administration of study treatment until death due to any cause, i.e.: (Date of death date of first administration of study treatment +1)/30.4375. Participants who did not have documented death from any cause were censored at the date they were last known to be alive. OS was added as an endpoint with Protocol Amendment #1, therefore, OS data was only collected from then onward. |
| Phase 2: Number of Participants With TEAEs | Up to a maximum of 131 weeks | AEs were defined as any untoward medical occurrence associated with the use of a drug in humans. TEAEs are defined as any AE that started on or after the first day of study treatment and within 30 days of the last administration of study treatment, or that worsened on or after the first day of study treatment. AE severity was graded according to the CTCAE version 5.0 on a scale from Grade 1 (mild) to Grade 5 (death). An AE was considered serious if it resulted in death, life-threatening AE, hospitalization or prolongation of hospitalization, persistent or significant incapacity, or congenital anomaly/birth defect. The Investigator determined relatedness to the use of onvansertib. Clinically significant changes in vital signs, laboratory parameters, electrocardiograms, physical examinations, weight, and ECOG performance status were reported as AEs. |
| Phase 2: Observed Plasma Concentration at the End of Each Dosing Interval (Ctrough) of Onvansertib | Pre-dose on Day 1 of Cycles 1 and 3 (28-day cycle length) | Plasma pharmacokinetic (PK) parameters for onvansertib were estimated using non-compartmental methods. |
| All-Treated Analysis Set: Percentage Change in KRAS-mutant Allelic Fraction (MAF) | Cycle 1 Day 1 and Cycle 2 Day 1 (28-day cycle length) | Blood samples were analyzed for the presence of circulating tumor DNA (ctDNA \[including KRAS mutations\]). KRAS-mutant allelic burden was based on liquid biopsies. |
| All-Treated Analysis Set: Disease Control Rate (DCR) | Up to a maximum of 131 weeks | DCR was defined as the percentage of participants documented to have a confirmed CR, PR or stable disease (SD) using the RECIST v1.1. Two-sided 95% CI was calculated using the exact binomial Clopper-Pearson method. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions. |
| All-Treated Analysis Set: Progression-free Survival (PFS) | Up to a maximum of 131 weeks | PFS was defined as the time in months from the date of first administration of study treatment until the first observation of PD or death due to any cause, whichever occurs first, i.e.: (date of first PD or death date of first administration of study treatment +1)/30.4375. Median and 95% CI were calculated using the Kaplan-Meier method. Participants who did not have an observed documented PD or death from any cause were censored at the latest tumor response assessment date. PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions. |
Countries
United States
Participant flow
Recruitment details
The study enrolled a total of 68 participants from 7 investigative sites in the United States between June 2019 and January 2024.
Participants by arm
| Arm | Count |
|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 Oral onvansertib 12 mg/m\^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m\^2 irinotecan, 400 mg/m\^2 leucovorin, 400 mg/m\^2 bolus 5-fluorouracil (5-FU), and 2400 mg/m\^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab. | 9 |
| Phase 1b: Onvansertib 15 mg/m^2 Oral onvansertib 15 mg/m\^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m\^2 irinotecan, 400 mg/m\^2 leucovorin, 400 mg/m\^2 bolus 5-FU, and 2400 mg/m\^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab. | 7 |
| Phase 1b: Onvansertib 18 mg/m^2 Oral onvansertib 18 mg/m\^2 received on Days 1 through 5 and Days 15 through 19 of each 28-day cycle in combination with FOLFIRI (180 mg/m\^2 irinotecan, 400 mg/m\^2 leucovorin, 400 mg/m\^2 bolus 5-FU, and 2400 mg/m\^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab. | 6 |
| Phase 2: Onvansertib 15 mg/m^2 Oral onvansertib RP2D of 15 mg/m\^2 received on Days 1 through 5 and Days 15 through 19 of every 28-day cycle in combination with FOLFIRI (180 mg/m\^2 irinotecan, 400 mg/m\^2 leucovorin, 400 mg/m\^2 bolus 5-FU, and 2400 mg/m\^2 continuous intravenous infusion 5-FU + 5 mg/kg bevacizumab, with treatment modifications or delays based on unresolved toxicity experienced during a previous cycle. | 46 |
| Total | 68 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 1 | 0 | 1 | 4 |
| Overall Study | Disease Progressing | 3 | 4 | 2 | 31 |
| Overall Study | Miscellaneous | 2 | 4 | 3 | 10 |
| Overall Study | Physician Decision | 0 | 0 | 0 | 2 |
Baseline characteristics
| Characteristic | Phase 1b: Onvansertib 12 mg/m^2 | Total | Phase 2: Onvansertib 15 mg/m^2 | Phase 1b: Onvansertib 18 mg/m^2 | Phase 1b: Onvansertib 15 mg/m^2 |
|---|---|---|---|---|---|
| Age, Continuous | 60.3 years STANDARD_DEVIATION 10.75 | 56.3 years STANDARD_DEVIATION 11.08 | 55.0 years STANDARD_DEVIATION 9.82 | 57.5 years STANDARD_DEVIATION 16.93 | 59.0 years STANDARD_DEVIATION 14.39 |
| Body Surface Area | 1.99 m^2 STANDARD_DEVIATION 0.315 | 1.96 m^2 STANDARD_DEVIATION 0.277 | 1.97 m^2 STANDARD_DEVIATION 0.264 | 2.02 m^2 STANDARD_DEVIATION 0.316 | 1.82 m^2 STANDARD_DEVIATION 0.293 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 7 Participants | 6 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 8 Participants | 59 Participants | 39 Participants | 5 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 7 Participants | 3 Participants | 2 Participants | 0 Participants |
| Race/Ethnicity, Customized Black or African American | 0 Participants | 3 Participants | 3 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Not Reported | 0 Participants | 1 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized Other | 1 Participants | 2 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race/Ethnicity, Customized White | 6 Participants | 54 Participants | 38 Participants | 4 Participants | 6 Participants |
| Sex: Female, Male Female | 2 Participants | 31 Participants | 19 Participants | 3 Participants | 7 Participants |
| Sex: Female, Male Male | 7 Participants | 37 Participants | 27 Participants | 3 Participants | 0 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 7 | 0 / 6 | 1 / 46 |
| other Total, other adverse events | 9 / 9 | 7 / 7 | 6 / 6 | 46 / 46 |
| serious Total, serious adverse events | 2 / 9 | 3 / 7 | 1 / 6 | 17 / 46 |
Outcome results
Primary
All-Treated Analysis Set: Objective Response Rate (ORR)
ORR was defined as the percentage of participants documented to have a confirmed complete response (CR) or partial response (PR) using the Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST v1.1). Two-sided 95% confidence interval (CI) was calculated using the exact binomial Clopper-Pearson method. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.
Time frame: Up to a maximum of 131 weeks
Population: All-Treated Analysis Set: defined as participants who received at least 1 dose of assigned onvansertib in Cycle 1. Inclusive of the group of participants who were enrolled at 15 mg/m\^2 in Phase 1b and Phase 2 (Part 1 and Part 2) as pre-specified in SAP section 9.4.2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 | All-Treated Analysis Set: Objective Response Rate (ORR) | 42.9 percentage of participants |
| Phase 1b: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: Objective Response Rate (ORR) | 27.3 percentage of participants |
| Phase 1b: Onvansertib 18 mg/m^2 | All-Treated Analysis Set: Objective Response Rate (ORR) | 15.4 percentage of participants |
| Phase 1b and 2 Total: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: Objective Response Rate (ORR) | 26.4 percentage of participants |
Primary
Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs)
DLTs were defined as a Grade 4 hematologic adverse events (AEs), Grade ≥ 3 non-hematologic AEs that were considered related to the study drug and that did not resolve within 14 days following presentation with standard management and care, Grade ≥ 3 thrombocytopenia with bleeding, neutropenic fever, any death not clearly due to the underlying disease or extraneous causes, or any change in liver function that met Hy's Law criteria of a DLT.
Time frame: Up to Day 28
Population: Safety Analysis Set: defined as participants who received at least one dose of onvansertib in any cycle. Three participants enrolled in 15 mg/m\^2 (2 in Phase 2 and 1 in Phase 1b) were inadvertently dosed at 12 mg/m\^2 and are represented under Phase 1b 12 mg/m\^2, as pre-specified in SAP section 9.4.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) | 1 Participants |
| Phase 1b: Onvansertib 15 mg/m^2 | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) | 1 Participants |
| Phase 1b: Onvansertib 18 mg/m^2 | Phase 1b: Number of Participants With Dose-limiting Toxicities (DLTs) | 3 Participants |
Primary
Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs)
AEs were defined as any untoward medical occurrence associated with the use of a drug in humans. TEAEs are defined as any AE that started on or after the first day of study treatment and within 30 days of the last administration of study treatment, or that worsened on or after the first day of study treatment. AE severity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 on a scale from Grade 1 (mild) to Grade 5 (death). An AE was considered serious if it resulted in death, life-threatening AE, hospitalization or prolongation of hospitalization, persistent or significant incapacity, or congenital anomaly/birth defect. The Investigator determined relatedness to the use of onvansertib. Clinically significant changes in vital signs, laboratory parameters, electrocardiograms, physical examinations, weight, and Eastern Cooperative Oncology Group (ECOG) performance status were reported as AEs.
Time frame: Up to a maximum of 81 weeks
Population: Safety Analysis Set: defined as participants who received at least one dose of onvansertib in any cycle. Three participants enrolled in 15 mg/m\^2 (2 in Phase 2 and 1 in Phase 1b) were inadvertently dosed at 12 mg/m\^2 and are represented under Phase 1b 12 mg/m\^2, as pre-specified in SAP section 9.4.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 9 Participants |
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE Related to Onvansertib | 8 Participants |
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE CTCAE Grade ≥3 | 7 Participants |
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE CTCAE Grade ≥3 Related to Onvansertib | 4 Participants |
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any Serious TEAE | 2 Participants |
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any Serious TEAE Related to Onvansertib | 0 Participants |
| Phase 1b: Onvansertib 15 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any Serious TEAE Related to Onvansertib | 0 Participants |
| Phase 1b: Onvansertib 15 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 7 Participants |
| Phase 1b: Onvansertib 15 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE CTCAE Grade ≥3 Related to Onvansertib | 1 Participants |
| Phase 1b: Onvansertib 15 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any Serious TEAE | 3 Participants |
| Phase 1b: Onvansertib 15 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE Related to Onvansertib | 7 Participants |
| Phase 1b: Onvansertib 15 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE CTCAE Grade ≥3 | 6 Participants |
| Phase 1b: Onvansertib 18 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE Related to Onvansertib | 4 Participants |
| Phase 1b: Onvansertib 18 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE CTCAE Grade ≥3 | 4 Participants |
| Phase 1b: Onvansertib 18 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any Serious TEAE Related to Onvansertib | 0 Participants |
| Phase 1b: Onvansertib 18 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE CTCAE Grade ≥3 Related to Onvansertib | 1 Participants |
| Phase 1b: Onvansertib 18 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any TEAE | 6 Participants |
| Phase 1b: Onvansertib 18 mg/m^2 | Phase 1b: Number of Participants With Treatment-emergent Adverse Events (TEAEs) | Any Serious TEAE | 1 Participants |
Secondary
All-Treated Analysis Set: Disease Control Rate (DCR)
DCR was defined as the percentage of participants documented to have a confirmed CR, PR or stable disease (SD) using the RECIST v1.1. Two-sided 95% CI was calculated using the exact binomial Clopper-Pearson method. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD). PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions.
Time frame: Up to a maximum of 131 weeks
Population: All-Treated Analysis Set: defined as participants who received at least 1 dose of assigned onvansertib in Cycle 1. Inclusive of the group of participants who were enrolled at 15 mg/m\^2 in Phase 1b and Phase 2 (Part 1 and Part 2) as pre-specified in SAP section 9.4.2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 | All-Treated Analysis Set: Disease Control Rate (DCR) | 100 percentage of participants |
| Phase 1b: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: Disease Control Rate (DCR) | 90.9 percentage of participants |
| Phase 1b: Onvansertib 18 mg/m^2 | All-Treated Analysis Set: Disease Control Rate (DCR) | 92.3 percentage of participants |
| Phase 1b and 2 Total: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: Disease Control Rate (DCR) | 92.5 percentage of participants |
Secondary
All-Treated Analysis Set: Duration of Response (DoR)
DoR was calculated as the (date of first documented tumor progression or death due to any cause minus date of first documentation of a subsequently confirmed objective response plus 1)/30.4375. Participants who did not have an observed documented PD or death from any cause were censored at the latest tumor response assessment date.
Time frame: Up to a maximum of 131 weeks
Population: All-Treated Analysis Set: defined as participants who received at least 1 dose of assigned onvansertib in Cycle 1. Inclusive of the group of participants who were enrolled at 15 mg/m\^2 in Phase 1b and Phase 2 (Part 1 and Part 2) as pre-specified in SAP section 9.4.2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 | All-Treated Analysis Set: Duration of Response (DoR) | 12 months |
| Phase 1b: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: Duration of Response (DoR) | 12 months |
| Phase 1b: Onvansertib 18 mg/m^2 | All-Treated Analysis Set: Duration of Response (DoR) | NA months |
| Phase 1b and 2 Total: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: Duration of Response (DoR) | 12 months |
Secondary
All-Treated Analysis Set: Overall Survival (OS)
OS was defined as the time in months from the date of first administration of study treatment until death due to any cause, i.e.: (Date of death date of first administration of study treatment +1)/30.4375. Participants who did not have documented death from any cause were censored at the date they were last known to be alive. OS was added as an endpoint with Protocol Amendment #1, therefore, OS data was only collected from then onward.
Time frame: Up to a maximum of 131 weeks
Population: All-Treated Analysis Set: defined as participants who received at least 1 dose of assigned onvansertib in Cycle 1. Inclusive of the group of participants who were enrolled at 15 mg/m\^2 in Phase 1b and Phase 2 (Part 1 and Part 2) as pre-specified in SAP section 9.4.2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 | All-Treated Analysis Set: Overall Survival (OS) | NA months |
| Phase 1b: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: Overall Survival (OS) | NA months |
| Phase 1b: Onvansertib 18 mg/m^2 | All-Treated Analysis Set: Overall Survival (OS) | NA months |
| Phase 1b and 2 Total: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: Overall Survival (OS) | NA months |
Secondary
All-Treated Analysis Set: Percentage Change in KRAS-mutant Allelic Fraction (MAF)
Blood samples were analyzed for the presence of circulating tumor DNA (ctDNA \[including KRAS mutations\]). KRAS-mutant allelic burden was based on liquid biopsies.
Time frame: Cycle 1 Day 1 and Cycle 2 Day 1 (28-day cycle length)
Population: All-Treated Analysis Set: defined as participants who received at least 1 dose of assigned onvansertib in Cycle 1. Inclusive of the group of participants who were enrolled at 15 mg/m\^2 in Phase 1b and Phase 2 (Part 1 and Part 2) as pre-specified in SAP section 9.4.2. Only participants with available data at Cycle 1 Day 1 and Cycle 2 Day 1 are represented.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 | All-Treated Analysis Set: Percentage Change in KRAS-mutant Allelic Fraction (MAF) | -85.5857 percentage change in MAF | Standard Deviation 19.442 |
| Phase 1b: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: Percentage Change in KRAS-mutant Allelic Fraction (MAF) | -76.2323 percentage change in MAF | Standard Deviation 26.43313 |
| Phase 1b: Onvansertib 18 mg/m^2 | All-Treated Analysis Set: Percentage Change in KRAS-mutant Allelic Fraction (MAF) | -62.0000 percentage change in MAF | Standard Deviation 33.72414 |
| Phase 1b and 2 Total: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: Percentage Change in KRAS-mutant Allelic Fraction (MAF) | -74.9000 percentage change in MAF | Standard Deviation 27.4574 |
Secondary
All-Treated Analysis Set: Progression-free Survival (PFS)
PFS was defined as the time in months from the date of first administration of study treatment until the first observation of PD or death due to any cause, whichever occurs first, i.e.: (date of first PD or death date of first administration of study treatment +1)/30.4375. Median and 95% CI were calculated using the Kaplan-Meier method. Participants who did not have an observed documented PD or death from any cause were censored at the latest tumor response assessment date. PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions.
Time frame: Up to a maximum of 131 weeks
Population: All-Treated Analysis Set: defined as participants who received at least 1 dose of assigned onvansertib in Cycle 1. Inclusive of the group of participants who were enrolled at 15 mg/m\^2 in Phase 1b and Phase 2 (Part 1 and Part 2) as pre-specified in SAP section 9.4.2.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 | All-Treated Analysis Set: Progression-free Survival (PFS) | 18 months |
| Phase 1b: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: Progression-free Survival (PFS) | 6 months |
| Phase 1b: Onvansertib 18 mg/m^2 | All-Treated Analysis Set: Progression-free Survival (PFS) | 8 months |
| Phase 1b and 2 Total: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: Progression-free Survival (PFS) | 8 months |
Secondary
Phase 2: Number of Participants With TEAEs
AEs were defined as any untoward medical occurrence associated with the use of a drug in humans. TEAEs are defined as any AE that started on or after the first day of study treatment and within 30 days of the last administration of study treatment, or that worsened on or after the first day of study treatment. AE severity was graded according to the CTCAE version 5.0 on a scale from Grade 1 (mild) to Grade 5 (death). An AE was considered serious if it resulted in death, life-threatening AE, hospitalization or prolongation of hospitalization, persistent or significant incapacity, or congenital anomaly/birth defect. The Investigator determined relatedness to the use of onvansertib. Clinically significant changes in vital signs, laboratory parameters, electrocardiograms, physical examinations, weight, and ECOG performance status were reported as AEs.
Time frame: Up to a maximum of 131 weeks
Population: Safety Analysis Set: defined as participants who received at least one dose of onvansertib in any cycle. Two participants from Phase 2 15 mg/m\^2 were inadvertently dosed at 12 mg/m\^2 dose level, as pre-specified in SAP section 9.4.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 2: Number of Participants With TEAEs | Any TEAE | 46 Participants |
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 2: Number of Participants With TEAEs | Any TEAE Related to Onvansertib | 26 Participants |
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 2: Number of Participants With TEAEs | Any TEAE CTCAE Grade ≥3 | 32 Participants |
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 2: Number of Participants With TEAEs | Any TEAE CTCAE Grade ≥3 Related to Onvansertib | 8 Participants |
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 2: Number of Participants With TEAEs | Any Serious TEAE | 17 Participants |
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 2: Number of Participants With TEAEs | Any Serious TEAE Related to Onvansertib | 1 Participants |
Secondary
Phase 2: Observed Plasma Concentration at the End of Each Dosing Interval (Ctrough) of Onvansertib
Plasma pharmacokinetic (PK) parameters for onvansertib were estimated using non-compartmental methods.
Time frame: Pre-dose on Day 1 of Cycles 1 and 3 (28-day cycle length)
Population: PK Analysis Set: defined as all participants in the safety analysis set who had at least one evaluable plasma concentration of onvansertib.
| Arm | Measure | Group | Value (MEAN) | Dispersion |
|---|---|---|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 2: Observed Plasma Concentration at the End of Each Dosing Interval (Ctrough) of Onvansertib | Cycle 1 Day 1 | 0.0000 ng/mL | Standard Deviation 0 |
| Phase 1b: Onvansertib 12 mg/m^2 | Phase 2: Observed Plasma Concentration at the End of Each Dosing Interval (Ctrough) of Onvansertib | Cycle 3 Day 1 | 0.3406 ng/mL | Standard Deviation 0.34496 |
Post Hoc
All-Treated Analysis Set: ORR by Bevacizumab Used in First-line Treatment
ORR was defined as the percentage of participants documented to have a confirmed CR or PR using the RECIST v1.1. Two-sided 95% CI was calculated using the exact binomial Clopper-Pearson method. Data are presented by bevacizumab used in first-line treatment yes versus no. CR: disappearance of all target and non-target lesions. Any pathological lymph nodes (whether target or non-target) must have had a reduction in short axis to \< 10 mm. All lymph nodes must have been non-pathological in size (\< 10mm short axis). PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the Baseline sum diameters.
Time frame: Up to a maximum of 131 weeks
Population: All-Treated Analysis Set: defined as participants who received at least 1 dose of assigned onvansertib in Cycle 1. Inclusive of the group of participants who were enrolled at 15 mg/m\^2 in Phase 1b and Phase 2 (Part 1 and Part 2) as pre-specified in SAP section 9.4.2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 | All-Treated Analysis Set: ORR by Bevacizumab Used in First-line Treatment | 42.9 percentage of participants |
| Phase 1b: Onvansertib 18 mg/m^2 | All-Treated Analysis Set: ORR by Bevacizumab Used in First-line Treatment | 4.5 percentage of participants |
| Phase 1b and 2 Total: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: ORR by Bevacizumab Used in First-line Treatment | 72.7 percentage of participants |
| Phase 2 Part 2; Bevacizumab Used in First-line Treatment: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: ORR by Bevacizumab Used in First-line Treatment | 0 percentage of participants |
| Phase 2 Part 2; Bevacizumab Not Used in First-line Treatment: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: ORR by Bevacizumab Used in First-line Treatment | 100 percentage of participants |
| Phase 1b and 2 Total; Bevacizumab Used in First-line Treatment: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: ORR by Bevacizumab Used in First-line Treatment | 10.0 percentage of participants |
| Phase 1b and 2 Total; Bevacizumab Not Used in First-line Treatment: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: ORR by Bevacizumab Used in First-line Treatment | 76.9 percentage of participants |
Post Hoc
All-Treated Analysis Set: PFS by Bevacizumab Used in First-line Treatment
PFS was defined as the time in months from the date of first administration of study treatment until the first observation of PD or death due to any cause, whichever occurs first, i.e.: (date of first PD or death date of first administration of study treatment +1)/30.4375. Median and 95% CI were calculated using the Kaplan-Meier method. Participants who did not have an observed documented PD or death from any cause were censored at the latest tumor response assessment date. Data are presented by bevacizumab used in first-line treatment yes versus no. PD: at least a 20% increase in the sum of diameters of target lesions. The sum must also demonstrate an increase of at least 5mm. Unequivocal progression of existing non-target lesions.
Time frame: Up to a maximum of 131 weeks
Population: All-Treated Analysis Set: defined as participants who received at least 1 dose of assigned onvansertib in Cycle 1. Inclusive of the group of participants who were enrolled at 15 mg/m\^2 in Phase 1b and Phase 2 (Part 1 and Part 2) as pre-specified in SAP section 9.4.2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1b: Onvansertib 12 mg/m^2 | All-Treated Analysis Set: PFS by Bevacizumab Used in First-line Treatment | 18 percentage of participants |
| Phase 1b: Onvansertib 18 mg/m^2 | All-Treated Analysis Set: PFS by Bevacizumab Used in First-line Treatment | 6 percentage of participants |
| Phase 1b and 2 Total: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: PFS by Bevacizumab Used in First-line Treatment | 15 percentage of participants |
| Phase 2 Part 2; Bevacizumab Used in First-line Treatment: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: PFS by Bevacizumab Used in First-line Treatment | 8 percentage of participants |
| Phase 2 Part 2; Bevacizumab Not Used in First-line Treatment: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: PFS by Bevacizumab Used in First-line Treatment | NA percentage of participants |
| Phase 1b and 2 Total; Bevacizumab Used in First-line Treatment: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: PFS by Bevacizumab Used in First-line Treatment | 6 percentage of participants |
| Phase 1b and 2 Total; Bevacizumab Not Used in First-line Treatment: Onvansertib 15 mg/m^2 | All-Treated Analysis Set: PFS by Bevacizumab Used in First-line Treatment | 15 percentage of participants |