Nab-Sirolimus in Combination With FOLFOX & BEV as 1st Line Therapy in Patients With Advanced or Metastatic Colorectal Cancer

Phase 1

Completed

• Conditions: Colorectal Cancer Metastatic
• Interventions: Drug: nab-sirolimus

• Registration Number: NCT03439462
• Lead Sponsor: Aadi Bioscience, Inc.

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.

Study Timeline

• Study First Submitted: 2018-02-08
• Study First Submitted QC: 2018-02-13
• Study First Posted: 2018-02-20
• Study Start: 2018-07-01
• Primary Completion: 2022-08-16
• Study Completion: 2022-08-26
• Results First Submitted: 2023-08-25
• Status Verified: 2023-11
• Results First Submitted QC: 2023-11-30
• Last Update Submitted: 2023-11-30
• Results First Posted: 2024-01-02
• Last Update Posted: 2024-01-02

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 60

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.

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
nab-sirolimus (also known as ABI-009, nab-rapamycin, albumin-bound rapamycin)	nab-sirolimus	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 CRC.

Primary Outcome Measures

Name	Time	Method
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 Outcome Measures

Name	Time	Method
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.

Trial Locations

Locations (6)

HonorHealth Research Institute; 🇺🇸 Scottsdale, Arizona, United States

Ochsner Clinic Foundation; 🇺🇸 New Orleans, Louisiana, United States

Seattle Cancer Care Alliance/University of Washington Medical Center; 🇺🇸 Seattle, Washington, United States

Comprehensive Cancer Centers of Nevada; 🇺🇸 Las Vegas, Nevada, United States

Atlantic Health System/Morristown Medical Center; 🇺🇸 Morristown, New Jersey, United States

Baylor Scott and White University Medical Center; 🇺🇸 Dallas, Texas, United States