Metastatic Colorectal Cancer (mCRC)
Conditions
Keywords
Microsatellite Stable, Metastatic Colorectal Cancer
Brief summary
This is an open label, randomized, two arm, multi-center study to explore the effect of leronlimab on the overall response rate/ overall survival and safety and tolerability when used in combination with trifluridine and tipiracil + bevacizumab in patients with MSS, mCRC who have progressed on prior treatment, with optional open label leronlimab plus pembrolizumab cohort for participants who have documented disease progression during the initial treatment period of the study and who continue to meet the initial inclusion and exclusion criteria. The main questions this study aims to answer are: 1. Can leronlimab, in combination with standard of care therapies trifluridine and tipiracil+ bevacizumab, increase the objective response rate in participants with MSS, mCRC who have progressed on prior treatment before participating in the study. 2. In participants who have documented progressive disease during the initial treatment period of the study, what is the objective response rate when leronlimab is administered in combination with pembrolizumab. 3. Is leronlimab safe and well tolerated when used in combination with trifluridine and tipiracil+ bevacizumab or in combination with pembrolizumab.
Detailed description
This is an open label, randomized, two arm, multi-center study evaluating the efficacy, safety, and tolerability of leronlimab in combination with trifluridine and tipiracil + bevacizumab in participants with MSS, relapsed or refractory, mCRC who have received and progressed, or are intolerant to, at least two prior standard of care treatment regimes, which may have included fluoropyrimidine, oxaliplatin, or irinotecan chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy. Approximately 60 participants, 30 participants in each of two arms evaluating either 350 mg or 700 mg of leronlimab, who are 18 years of age or older, with histologically confirmed metastatic colorectal cancer that is microsatellite stable (MSS). Participants will be randomized 1:1 to each arm, where approximately 30 participants will receive 350 mg of leronlimab + trifluridine and tipiracil + bevacizumab and approximately 30 will receive 700 mg of leronlimab + trifluridine and tipiracil + bevacizumab. Participants who complete 52 weeks of treatment and have complete response (CR), partial response (PR), or stable disease (SD) according to RECIST v1.1, with no documented disease progression since their most recent tumor imaging assessment, may be eligible to enter an Extension Treatment Period and continue treatment for up to an additional 52 weeks. Participants entering the Extension Treatment Period will continue the same dose of leronlimab received during the initial treatment period in combination with trifluridine/tipiracil and bevacizumab. An optional open-label cohort will evaluate leronlimab in combination with pembrolizumab in participants who have documented disease progression during the initial treatment period of the study and meet the applicable eligibility criteria for the cohort. Participants entering this cohort will receive leronlimab 700 mg subcutaneously once weekly in combination with pembrolizumab 200 mg administered intravenously every 3 weeks. Approximately 12 participants may be enrolled in this cohort and may receive treatment for up to 48 weeks.
Interventions
Leronlimab (PRO) 140 is a humanized IgG4, monoclonal antibody (mAb) to the C-C chemokine receptor type 5 (CCR5)
Leronlimab (PRO) 140 is a humanized IgG4, monoclonal antibody (mAb) to the C-C chemokine receptor type 5 (CCR5)
Pembrolizumab is a humanized monoclonal antibody that binds to the programmed death receptor-1 (PD-1) and blocks its interaction with PD-L1 and PD-L2.
Sponsors
CytoDyn, Inc.
Syneos Health
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(Main Study): 1. Male or female subjects age ≥ 18 years with a history of treated colorectal cancer with unresectable metastases of the primary colorectal cancer to other organs. 2. If HIV-1 positive, (known or documented), viral load must be \< 50 copies/ml and the participant must be on stable ART for at least 3 months. HIV testing is not required for eligibility determination unless clinically indicated. 3. Adult patients with metastatic colorectal cancer (mCRC) received and progressed, or are intolerant, of at least two prior standard of care treatment regimes, which may have included fluoropyrimidine-, oxaliplatin-, or irinotecan chemotherapy, an anti-VEGF therapy, and, if RAS wild-type and medically appropriate, an anti-EGFR therapy. 4. Histologically confirmed for microsatellite stable MSS colorectal cancer by PCR, Immunohistochemistry (IHC) or Next-generation sequencing (NGS). 5. Have measurable disease per RECIST v1.1 6. Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 7. Expected survival of at least three months. 8. No anti-cancer treatment within the last two weeks or at least 5 half-lives prior to treatment (whichever is shorter), except for palliative radiation therapy from which the patient has recovered from all adverse events. 9. Patients must have adequate organ and bone marrow function within 28 days prior to the first dosing visit, defined as: i. Acceptable liver function: 1. Total bilirubin ≤ 1.5 × upper limit of normal (ULN) OR direct bilirubin ≤ ULN for participants with total bilirubin levels \> 1.5 × ULN (participants with known Gilbert's disease may enroll with Total bilirubin ≤ 2.5 × ULN AND direct bilirubin is ≤1.5 × ULN) (if liver metastases are present, Total bilirubin ≤2.0 × ULN). 2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN (≤ 5 × ULN for participants with liver metastases). ii. Acceptable renal function: a) GFR ≥ 30 mL/min iii. Acceptable hematologic status: 1. Hemoglobin ≥ 9 g/dL Note: Criteria must be met without packed red blood cell (pRBC) transfusion within the prior 2 weeks. Participants can be on stable dose of erythropoietin (≥ approximately 3 months). 2. White blood cells \> 2500/µL 3. Absolute neutrophil count \> 1500/µL 4. Platelet count \> 100 000/µL. 10. Clinically normal resting 12-lead ECG at Screening Visit or, if abnormal, considered not clinically significant by the Principal Investigator. a) No QTC interval exceeding 460 milliseconds (ms) for females, no QTC interval exceeding 450 ms for males. 11. Both male and female patients and their partners of childbearing potential must agree to use two medically accepted methods of contraception (e.g., barrier contraceptives \[male condom, female condom, or diaphragm with a spermicidal gel\], hormonal contraceptives \[implants, injectables, combination oral contraceptives, transdermal patches, or contraceptive rings\], or one of the following methods of birth control (intrauterine devices, tubal sterilization or vasectomy) or must practice complete abstinence from intercourse of reproductive potential from study entry to 6 months after the last day of treatment (excluding women who are not of childbearing potential and men who have been sterilized). 12. Females of childbearing potential (FOCBP) must have a negative serum pregnancy test at Screening Visit and negative urine pregnancy test prior to receiving the first dose of study. 13. Male participants must agree to use contraception and refrain from donating sperm for at least 6 months after the last dose of study intervention. 14. Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study.
Exclusion criteria
(Main Study): 1. Known severe hypersensitivity towards monoclonal antibodies. 2. Clinically significant, active coronary heart disease and cardiovascular insufficiency with compromised hemodynamics per PI discretion. 3. Had a known additional malignancy that was progressing or had required active treatment within the past 2 years. Note: Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin, incidentally diagnosed prostate cancer (i.e., during a TURP), carcinoma in situ (breast or cervical), excluding carcinoma in situ of bladder, that had undergone potentially curative therapy are not excluded. 4. Active hepatitis B (defined as having a positive hepatitis B surface antigen \[HBsAg\] test) or active hepatitis C infection (defined as detectable hepatitis C virus \[HCV\] RNA), or other known or suspected viral infections. Routine HBsAg/HCV screening is not mandated; however, participants with known or suspected infection are excluded. 5. Are pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the study, starting with the Screening Visit through 120 days after the last dose of study intervention. 6. Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial. 7. Stroke and/or transient ischemic attack within 6 months prior to screening. 8. Placement of a cardiac stent or bypass surgery within 6 months of screening. 9. Tumor invasion of a large vascular structure (e.g., pulmonary artery, superior or inferior vena cava). 10. Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study treatment. Note: Participants who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. 11. Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy. 12. Inability to follow protocol. 13. Patients who received Trifluridine + Tipiracil (TAS-102) prior to receiving first study drug dose. 14. Serious non-malignant or malignant disease (e.g. hepatic compromise, obstructive hydronephrosis, or other conditions which may worsen) that could compromise study objectives in the opinion of the investigator, including recurrent ascites or pleural effusion requiring more than one paracentesis or thoracentesis or a single paracentesis or thoracentesis removing more than 3.0 liters of ascites within 30 days prior to screening. Inclusion Criteria (Extension Cohort): All inclusion criteria applicable to the two main study treatment arms (leronlimab 350 mg and leronlimab 700 mg, each in combination with Trifluridine + Tipiracil \[TAS-102\] and bevacizumab) apply, except Inclusion Criterion #8. Continued treatment with Trifluridine + Tipiracil (TAS-102), with or without bevacizumab, from the main study is allowed.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The efficacy of leronlimab in combination with trifluridine and tipiracil + bevacizumab in participants with relapsed, refractory, MSS, mCRC. | From enrolment through end of treatment at 12 months | Efficacy will be measured as the effect on objective response rate (ORR) of leronlimab when used in combination with trifluridine and tipiracil + bevacizumab in patients with relapsed, refractory, MSS, mCRC. ORR is defined as the proportion of subjects with the best overall response (BOR) or confirmed CR or confirmed PR according to RECIST v1.1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The efficacy of leronlimab in combination with pembrolizumab in participants with MSS, mCRC who have documented progressive disease (PD) during the initial treatment period of the study. | From initiation of treatment in the leronlimab plus pembrolizumab cohort through end of treatment, up to 48 weeks. | Efficacy will be measured as the effect on objective response rate (ORR) of leronlimab when used in combination with pembrolizumab in participants with MSS, mCRC who entered the leronlimab plus pembrolizumab cohort. ORR is defined as the proportion of subjects with the best overall response (BOR) or confirmed CR or confirmed PR according to RECIST v1.1. |
| Assessment of safety and tolerability of leronlimab when used in combination with trifluridine and tipiracil + bevacizumab or in combination with pembrolizumab in patients with relapsed, refractory, MSS, mCRC. | From enrollment through end of treatment, up to approximately 24 months. | Treatment Emergent AE's (TEAE) are defined as events with an onset on or after the first treatment. TEAEs will be summarized by treatment group, System Organ Class, and preferred term. The following TEAE summaries will be provided: * All TEAEs * TEAEs related to study drug. * All TEAEs by severity * Serious TEAEs * Serious TEAEs related to study drug. * TEAE reported in 5% or more participants in any treatment group. * TEAEs leading to discontinuation of study treatment. * TEAEs leading to interruption of study treatment. * TEAEs leading to death. |
| Assessment of the duration of response (DOR) of leronlimab in combination with trifluridine and tipiracil + bevacizumab and leronlimab in combination with pembrolizumab in participants with relapsed, refractory, MSS, mCRC. | From enrolment through end of treatment, up to 48 weeks. | The time from the first documentation of response, either partial or complete, to the documentation of the objective tumor progression or until death due to any cause. |
| Assessment of PK parameters of leronlimab during the 12-month treatment period. | From enrolment through end of treatment at 12 months. | PK parameters will be calculated following multiple dosing during the Treatment Period (12 months) and will include the following: * Cmax, Tmax, AUC0-168, AUC0-last, and AUC0-τ, trough concentrations * AUC0-inf, t1/2, CL/F, and Vz/F. |
| Evaluation of immunogenicity of leronlimab during treatment period and follow-up. | From enrolment through 12 months and approximately 30 days post treatment follow-up. | Incidence of Anti-Drug-Antibodies from pre-dose baseline through 52 weeks of treatment and approximately 30 days post treatment during follow-up. Incidence of Neutralizing Antibodies from pre-dose baseline through 52 weeks of treatment and approximately 30 days post treatment during follow-up. |
| Assessment of the DCR (disease control rate) per RECIST criteria (v1.1) for leronlimab in combination with trifluridine and tipiracil + bevacizumab and with pembrolizumab of patients with relapsed, refractory, mCRC. | From enrolment through end of treatment at 24 months. | The proportion of participants with complete response (CR), partial response (PR), or stable disease (SD) lasting at least 6 weeks as their best overall response during treatment, as determined according to RECIST v1.1. |
| Assessment of individual progression free survival (PFS). | From first treatment through end of study (up to 160 weeks) | Time from the date of first treatment to the first documented objective radiographic tumor progression per RECIST v1.1 or death from any cause, whichever occurs first. |
| Assessment of individual overall survival (OS). | From first treatment through end of study (up to 160 weeks). | Time from date of first treatment until death from any cause. |
Countries
United States
Outcome results
None listed