Colorectal Cancer Metastatic
Conditions
Brief summary
A phase 1/2 multi-center investigation of nab-sirolimus (also known as ABI-009, nab-rapamycin) in combination with mFOLFOX6 and Bevacizumab as first-line therapy in patients with metastatic colorectal cancer
Detailed description
This study is a prospective phase 1/2, single arm, open-label, multi-institutional study to identify the RP2D and determine the efficacy and safety profile of nab-sirolimus administered as first-line therapy in combination with mFOLFOX6 and bevacizumab in patients with metastatic colorectal cancer.
Interventions
DRUGnab-sirolimus
nab-sirolimus combined with mFOLFOX6 + bevacizumab
Sponsors
Aadi Bioscience, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 85 Years
Healthy volunteers
No
Inclusion criteria
1. Patients with histologically confirmed advanced or metastatic colorectal cancers for whom chemotherapy is indicated. 2. Patients must not have had prior chemotherapy for advanced or metastatic disease. Patients could have received adjuvant chemotherapy or adjuvant chemo-radiotherapy. 3. Patients must have at least 1 measurable site of disease according to RECIST v1.1 that has not been previously irradiated. If the patient has had previous radiation to the marker lesion(s), there must be radiological evidence of progression since the radiation. 4. Eligible patients, 18 years or older, with Eastern Cooperative Oncology Group (ECOG) performance status 0, 1, or 2. 5. Patients must not have been previously treated with an mTOR inhibitor. 6. Adequate liver function: 1. Total bilirubin ≤1.5 x upper limit of normal (ULN) mg/dL 2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 x ULN (\<5 x ULN if the patient has liver metastases). 7. Adequate renal function: a. Serum creatinine ≤2 x ULN or creatinine clearance \>50 cc/hr (Cockroft-Gault). 8. Adequate biological parameters: 1. Absolute neutrophil count (ANC) ≥1.5 × 109/L 2. Platelet count ≥100,000/mm3 (100 × 109/L) 3. Hemoglobin ≥9 g/dL. 9. Fasting serum triglyceride ≤300 mg/dL; fasting serum cholesterol ≤350 mg/dL. 10. INR and PTT \<1.5 x ULN (anticoagulation is allowed if target INR \<1.5 on a stable dose of warfarin or on a stable dose of LMW heparin for \>2 weeks at time of enrollment). 11. Minimum of 4 weeks since any major surgery, completion of radiation, or completion of all prior systemic anticancer therapy, and ≥6 months since adjuvant FOLFOX therapy (adequately recovered from the acute toxicities of any prior therapy, including neuropathy should be grade ≤1). 12. Male or non-pregnant and non-breast feeding female: * Females of child-bearing potential must agree to use effective contraception without interruption from 28 days prior to starting IP throughout 3 months after last dose of IP and have a negative serum pregnancy test (β -hCG) result at screening and agree to ongoing pregnancy testing during the course of the study, and after the end of study treatment. A second form of birth control is required even if she has had a tubal ligation. * Male patients must practice abstinence or agree to use a condom during sexual contact with a pregnant female or a female of childbearing potential while participating in the study and throughout 3 months after last dose of IP. A second form of birth control is required even if he has undergone a successful vasectomy. 13. Life expectancy of \>3 months, as determined by the investigator. 14. Ability to understand and sign informed consent. 15. Willingness and ability to comply with scheduled visits, laboratory tests, and other study procedures.
Exclusion criteria
1. History of severe and uncontrolled allergic reactions to bevacizumab 2. Prior treatment with FOLFOX or bevacizumab within the preceding 4 weeks 3. Patients currently receiving or have received anticancer therapies within 4 weeks of the start of study treatment (including chemotherapy, radiation therapy, antibody based therapy, etc.) 4. Patients, who have had a major surgery or significant traumatic injury within 4 weeks of start of study drug, patients who have not recovered from the side effects of any major surgery (defined as requiring general anesthesia) or patients that may require major surgery during the course of the study 5. Chronic treatment with systemic steroids or another immunosuppressive agent; topical or inhaled corticosteroids are allowed 6. Recent infection requiring systemic anti-infective treatment that was completed ≤14 days prior to enrollment (with the exception of uncomplicated urinary tract infection or upper respiratory tract infection). 7. Patients who have any severe and/or uncontrolled medical or psychiatric conditions or other conditions that could affect their participation including: 1. Known active uncontrolled or symptomatic central nervous system (CNS) metastases. A patient with controlled and asymptomatic CNS metastases may participate in this study. As such, the patient must have completed any prior treatment for CNS metastases ≥28 days (including radiotherapy and/or surgery) prior to start of treatment in this study and should not be receiving chronic corticosteroid therapy for the CNS metastases. 2. Unstable angina pectoris, symptomatic congestive heart failure, myocardial infarction ≤6 months prior to first study treatment, serious uncontrolled cardiac arrhythmia or any other clinically significant cardiac disease 3. Pre-existing severely impaired lung function as defined as spirometry and DLCO that is 50% of the normal predicted value and/or O2 saturation that is 88% or less at rest on room air (Note: spirometry and PFTs not required to be performed unless clinically indicated). 4. Uncontrolled diabetes as defined by fasting serum glucose \>1.5x ULN or by HbA1c \>8% despite adequate therapy. 5. Any active (acute or chronic) or uncontrolled infection/ disorders. 6. Nonmalignant medical illnesses that are uncontrolled or whose control may be jeopardized by the treatment with the study therapy. Note, controlled non-melanoma skin cancers, carcinoma in situ of the cervix, resected incidental prostate cancer, or other adequately treated carcinoma-in-situ may be eligible, after documented discussion with the sponsor / medical monitor. 7. Known liver disease such as cirrhosis or severe hepatic impairment (Child-Pugh class C). 8. Patients with history of interstitial lung disease and/or pneumonitis, or pulmonary hypertension. 9. A known history of HIV seropositivity. 10. Active Hepatitis B or Hepatitis C. Note: A detailed assessment of Hepatitis B/C medical history and risk factors must be done at screening for all patients. HBV DNA and HCV RNA PCR testing are required at screening for all patients with a positive medical history based on risk factors and/or confirmation of prior HBV/HCV infection. 11. Patients with an active bleeding diathesis or on oral anti-vitamin K medication (except low dose Coumadin). 12. Use of strong inhibitors and inducers of CYP3A4 within the 14 days prior to receiving the first dose of ABI-009. Additionally, use of any known CYP3A4 substrates with narrow therapeutic window (such as fentanyl, alfentanil, astemizole, cisapride, dihydroergotamine, pimozide, quinidine, terfanide) within the 14 days prior to receiving the first dose of ABI-009.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose-limiting-toxicities (DLTs) (Phase 1) | First 2 treatment cycles (2 months) | Dose-limiting-toxicities within the first 2 cycles of treatment with nab-sirolimus at various doses and schedule in combination with mFOLFOX6 and bevacizumab |
| Progression-free Survival at 6 Months (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 6 months | The PFS rate at 6 months was estimated using the Kaplan-Meier method for a) all efficacy evaluable patients, b) patients receiving treatment at the RP2D, and c) based on PTEN status (positive or negative). Progression-free survival was defined as the time from the first day of study drug administration to disease progression or death due to any cause. Response evaluation was performed per RECIST v1.1, with the criteria for progression is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Disease Control Rate (DCR) (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | Through study completion (up to 50 months) | Disease control rate is defined as patients who achieved complete response, partial response, or stable disease and was summarized for a) all efficacy evaluable patients, b) patients receiving treatment at the RP2D, and c) based on PTEN status (positive or negative). Complete response and partial response required confirmation of response at the subsequent tumor assessment. Stable disease required a confirmatory assessment at a minimum interval of 8 weeks |
| Median Progression-free Survival (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | Through study completion (up to 50 months) | The median PFS was estimated using the Kaplan-Meier method for a) all efficacy evaluable patients, b) patients receiving treatment at the RP2D, and c) based on PTEN status (positive or negative). Progression-free survival was defined as the time from the first day of study drug administration to disease progression or death due to any cause. Response evaluation was performed per RECIST v1.1, with the criteria for progression is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. |
| Overall Response Rate (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | Through study completion (up to 50 months) | The ORR was the proportion of patients who achieved a confirmed partial response or complete response per RECIST v1.1, and summarized for a) all efficacy evaluable patients, b) patients receiving treatment at the RP2D, and c) based on PTEN status (positive or negative). The ORR was reported along with exact 95% confidence intervals computed by the Clopper-Pearson method. Per RECIST v1.1, at each timepoint, objective tumor response for target lesions were assessed as such: Complete Response, disappearance of all target lesions, and pathological lymph nodes must have a reduction \<10 mm; Partial Response, ≥30% decrease in the sum of the longest diameter of target lesions. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1: Nab-Sirolimus 30 mg/m2 qw3/4 Dose /Schedule Cohort 1:
nab-Sirolimus: 30 mg/m2 weekly on Days 1, 8, and 15 (28-day cycle) by IV
Modified FOLFOX6 regimen: oxaliplatin 85 mg/m2 IV with LV 400 mg/m2 IV over 2 hours plus FU 400 mg/m2 IV bolus and 2,400 mg/m2 continuous infusion over 46 hours every 2 weeks
Bevacizumab: 5 mg/kg IV every 2 weeks | 6 |
| Cohort 1: Nab-Sirolimus 20 mg/m2 qw3/4 Dose /Schedule Cohort 2:
nab-Sirolimus: 20 mg/m2 weekly on Days 1, 8, and 15 (28-day cycle) by IV
Modified FOLFOX6 regimen: oxaliplatin 85 mg/m2 IV with LV 400 mg/m2 IV over 2 hours plus FU 400 mg/m2 IV bolus and 2,400 mg/m2 continuous infusion over 46 hours every 2 weeks.
Bevacizumab: 5 mg/kg IV every 2 weeks | 10 |
| Cohort 2: Nab-Sirolimus 20 mg/m2 qw2/4 Dose /Schedule Cohort 3: (Recommended Phase 2 Dose, RP2D):
nab-Sirolimus: 20 mg/m2 every 2 weeks (28-day cycle) by IV.
Modified FOLFOX6 regimen: oxaliplatin 85 mg/m2 IV with LV 400 mg/m2 IV over 2 hours plus FU 400 mg/m2 IV bolus and 2,400 mg/m2 continuous infusion over 46 hours every 2 weeks
Bevacizumab: 5 mg/kg IV every 2 weeks | 44 |
| Total | 60 |
Baseline characteristics
| Characteristic | Cohort 1: Nab-Sirolimus 30 mg/m2 qw3/4 | Cohort 1: Nab-Sirolimus 20 mg/m2 qw3/4 | Cohort 2: Nab-Sirolimus 20 mg/m2 qw2/4 | Total |
|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 2 Participants | 1 Participants | 10 Participants | 13 Participants |
| Age, Categorical Between 18 and 65 years | 4 Participants | 9 Participants | 34 Participants | 47 Participants |
| Age, Continuous | 61.5 Years | 46.0 Years | 51.0 Years | 51.0 Years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 5 Participants | 8 Participants | 41 Participants | 54 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants | 2 Participants | 2 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 1 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 2 Participants | 4 Participants | 6 Participants |
| Race (NIH/OMB) White | 6 Participants | 7 Participants | 36 Participants | 49 Participants |
| Region of Enrollment United States | 6 participants | 10 participants | 44 participants | 60 participants |
| Sex: Female, Male Female | 1 Participants | 5 Participants | 17 Participants | 23 Participants |
| Sex: Female, Male Male | 5 Participants | 5 Participants | 27 Participants | 37 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 / 6 | 1 / 10 | 3 / 44 | 4 / 60 |
| other Total, other adverse events | 6 / 6 | 9 / 10 | 44 / 44 | 59 / 60 |
| serious Total, serious adverse events | 0 / 6 | 2 / 10 | 5 / 44 | 7 / 60 |
Outcome results
Primary
Dose-limiting-toxicities (DLTs) (Phase 1)
Dose-limiting-toxicities within the first 2 cycles of treatment with nab-sirolimus at various doses and schedule in combination with mFOLFOX6 and bevacizumab
Time frame: First 2 treatment cycles (2 months)
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1: Nab-Sirolimus 30 mg/m2 qw3/4 | Dose-limiting-toxicities (DLTs) (Phase 1) | 0 Participants |
| Cohort 2: Nab-Sirolimus 20 mg/m2 qw3/4 | Dose-limiting-toxicities (DLTs) (Phase 1) | 0 Participants |
| Cohort 3: Nab-Sirolimus 20 mg/m2 qw2/4 | Dose-limiting-toxicities (DLTs) (Phase 1) | 0 Participants |
| All Patients | Dose-limiting-toxicities (DLTs) (Phase 1) | 0 Participants |
Primary
Progression-free Survival at 6 Months (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative)
The PFS rate at 6 months was estimated using the Kaplan-Meier method for a) all efficacy evaluable patients, b) patients receiving treatment at the RP2D, and c) based on PTEN status (positive or negative). Progression-free survival was defined as the time from the first day of study drug administration to disease progression or death due to any cause. Response evaluation was performed per RECIST v1.1, with the criteria for progression is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study.
Time frame: 6 months
Population: The Efficacy Analysis Set includes all patients at baseline who received ≥2 doses of nab-sirolimus and had ≥1 scan. Based on the statistical design of this Phase 1/2 study, the efficacy endpoints are analyzed together for All Efficacy Evaluable patients (n=56) and at the RP2D (n=41). The data for all efficacy evaluable patients was also prospectively evaluated based on PTEN status for those with available IHC results (positive or negative, n=39 and n=12, respectively).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Nab-Sirolimus 30 mg/m2 qw3/4 | Progression-free Survival at 6 Months (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 77.3 percentage of patients |
| Cohort 2: Nab-Sirolimus 20 mg/m2 qw3/4 | Progression-free Survival at 6 Months (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 76.3 percentage of patients |
| Cohort 3: Nab-Sirolimus 20 mg/m2 qw2/4 | Progression-free Survival at 6 Months (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 78.2 percentage of patients |
| All Patients | Progression-free Survival at 6 Months (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 82.5 percentage of patients |
Secondary
Disease Control Rate (DCR) (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative)
Disease control rate is defined as patients who achieved complete response, partial response, or stable disease and was summarized for a) all efficacy evaluable patients, b) patients receiving treatment at the RP2D, and c) based on PTEN status (positive or negative). Complete response and partial response required confirmation of response at the subsequent tumor assessment. Stable disease required a confirmatory assessment at a minimum interval of 8 weeks
Time frame: Through study completion (up to 50 months)
Population: The Efficacy Analysis Set includes all patients at baseline who received ≥2 doses of nab-sirolimus and had ≥1 scan. Based on the statistical design of this Phase 1/2 study, the efficacy endpoints are analyzed together for All Efficacy Evaluable patients (n=56) and at the RP2D (n=41). The data for all efficacy evaluable patients was also prospectively evaluated based on PTEN status for those with available IHC results (positive or negative, n=39 and n=12, respectively).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Nab-Sirolimus 30 mg/m2 qw3/4 | Disease Control Rate (DCR) (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 78.6 percentage of efficacy analysis patients |
| Cohort 2: Nab-Sirolimus 20 mg/m2 qw3/4 | Disease Control Rate (DCR) (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 75.6 percentage of efficacy analysis patients |
| Cohort 3: Nab-Sirolimus 20 mg/m2 qw2/4 | Disease Control Rate (DCR) (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 79.5 percentage of efficacy analysis patients |
| All Patients | Disease Control Rate (DCR) (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 83.3 percentage of efficacy analysis patients |
Secondary
Median Progression-free Survival (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative)
The median PFS was estimated using the Kaplan-Meier method for a) all efficacy evaluable patients, b) patients receiving treatment at the RP2D, and c) based on PTEN status (positive or negative). Progression-free survival was defined as the time from the first day of study drug administration to disease progression or death due to any cause. Response evaluation was performed per RECIST v1.1, with the criteria for progression is at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study.
Time frame: Through study completion (up to 50 months)
Population: The Efficacy Analysis Set includes all patients at baseline who received ≥2 doses of nab-sirolimus and had ≥1 scan. Based on the statistical design of this Phase 1/2 study, the efficacy endpoints are analyzed together for All Efficacy Evaluable patients (n=56) and at the RP2D (n=41). The data for all efficacy evaluable patients was also prospectively evaluated based on PTEN status for those with available IHC results (positive or negative, n=39 and n=12, respectively).
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Cohort 1: Nab-Sirolimus 30 mg/m2 qw3/4 | Median Progression-free Survival (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 10.9 Month |
| Cohort 2: Nab-Sirolimus 20 mg/m2 qw3/4 | Median Progression-free Survival (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 10.9 Month |
| Cohort 3: Nab-Sirolimus 20 mg/m2 qw2/4 | Median Progression-free Survival (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 13.1 Month |
| All Patients | Median Progression-free Survival (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 10.4 Month |
Secondary
Overall Response Rate (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative)
The ORR was the proportion of patients who achieved a confirmed partial response or complete response per RECIST v1.1, and summarized for a) all efficacy evaluable patients, b) patients receiving treatment at the RP2D, and c) based on PTEN status (positive or negative). The ORR was reported along with exact 95% confidence intervals computed by the Clopper-Pearson method. Per RECIST v1.1, at each timepoint, objective tumor response for target lesions were assessed as such: Complete Response, disappearance of all target lesions, and pathological lymph nodes must have a reduction \<10 mm; Partial Response, ≥30% decrease in the sum of the longest diameter of target lesions.
Time frame: Through study completion (up to 50 months)
Population: The Efficacy Analysis Set includes all patients at baseline who received ≥2 doses of nab-sirolimus and had ≥1 scan. Based on the statistical design of this Phase 1/2 study, the efficacy endpoints are analyzed together for All Efficacy Evaluable patients (n=56) and at the RP2D (n=41). The data for all efficacy evaluable patients was also prospectively evaluated based on PTEN status for those with available IHC results (positive or negative, n=39 and n=12, respectively).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1: Nab-Sirolimus 30 mg/m2 qw3/4 | Overall Response Rate (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 39.3 percentage of efficacy analysis patients |
| Cohort 2: Nab-Sirolimus 20 mg/m2 qw3/4 | Overall Response Rate (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 36.6 percentage of efficacy analysis patients |
| Cohort 3: Nab-Sirolimus 20 mg/m2 qw2/4 | Overall Response Rate (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 43.6 percentage of efficacy analysis patients |
| All Patients | Overall Response Rate (Phase 2) for All Patients, at the RP2D, as Well as Based on PTEN Status (Positive and Negative) | 41.7 percentage of efficacy analysis patients |