A Phase Two Study Evaluating Two Doses of Leronlimab (PRO 140) In Combination With Trifluridine + Tipiracil (TAS-102) + Bevacizumab in Participants With Microsatellite Stable (MSS), Relapsed Refractory Metastatic Colorectal Cancer (mCRC)
试验速览
- 阶段
- 2 期
- 状态
- 进行中（未招募）
- 入组人数
- 66
- 试验地点
- 13
- 主要终点
- To evaluate the efficacy of leronlimab in combination with trifluridine and tipiracil + bevacizumab in participants with CCR5+, refractory, MSS, mCRC.
研究概览
简要总结
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:
- 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.
- 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.
- Is leronlimab safe and well tolerated when used in combination with trifluridine and tipiracil+ bevacizumab or in combination with pembrolizumab.
详细描述
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.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Treatment
- 盲法
- None
入排标准
- 年龄范围
- 18 Years 至 —（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 否
入选标准
- •(Main Study):
- •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.
- •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.
- •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.
- •Histologically confirmed for microsatellite stable MSS colorectal cancer by PCR, Immunohistochemistry (IHC) or Next-generation sequencing (NGS).
- •Have measurable disease per RECIST v1.1
- •Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or
- •Expected survival of at least three months.
- •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.
- •Patients must have adequate organ and bone marrow function within 28 days prior to the first dosing visit, defined as:
- •i. Acceptable liver function:
- •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).
- •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:
- •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).
- •White blood cells > 2500/µL
- •Absolute neutrophil count > 1500/µL
- •Platelet count > 100 000/µL.
- •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.
- •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).
- •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.
- •Male participants must agree to use contraception and refrain from donating sperm for at least 6 months after the last dose of study intervention.
- •Patients must have the ability to understand and the willingness to sign a written informed consent prior to registration on study.
排除标准
- •(Main Study):
- •Known severe hypersensitivity towards monoclonal antibodies.
- •Clinically significant, active coronary heart disease and cardiovascular insufficiency with compromised hemodynamics per PI discretion.
- •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.
- •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.
- •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.
- •Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
- •Stroke and/or transient ischemic attack within 6 months prior to screening.
- •Placement of a cardiac stent or bypass surgery within 6 months of screening.
- •Tumor invasion of a large vascular structure (e.g., pulmonary artery, superior or inferior vena cava).
- •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.
- •Active, uncontrolled bacterial, viral, or fungal infections, requiring systemic therapy.
- •Inability to follow protocol.
- •Patients who received Trifluridine + Tipiracil (TAS-102) prior to receiving first study drug dose.
- •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 #
- •Continued treatment with Trifluridine + Tipiracil (TAS-102), with or without bevacizumab, from the main study is allowed.
- •Exclusion Criteria (Extension Cohort):
- •All exclusion 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 Exclusion Criteria #10 and #
- •Prior participation in the main study is allowed and continued treatment on Trifluridine + Tipiracil (TAS-102) with or without bevacizumab from the main study is allowed.
- •Inclusion Criteria (Leronlimab plus Pembrolizumab Cohort):
- •Meet all applicable inclusion criteria from the main study, except Item #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. Continued treatment on Trifluridine + Tipiracil (TAS-102) with or without bevacizumab from the main study is allowed.
- •Have adequately recovered from prior therapy, defined as resolution of all clinically significant treatment-related toxicities from prior trifluridine and tipiracil + bevacizumab to Grade ≤1 (or baseline).
- •Have received their last dose of trifluridine and tipiracil at least 3 weeks prior to the first dose of the leronlimab-pembrolizumab combination.
- •Have documented disease progression.
- •Provide written informed consent to participate in the pembrolizumab cohort.
- •Exclusion Criteria (Leronlimab plus Pembrolizumab Cohort):
- •Meet all applicable exclusion criteria from the main study, except Items #10 and #
- •Prior participation in the main study is allowed and continued treatment on Trifluridine + Tipiracil (TAS-102) with or without bevacizumab from the main study is allowed.
- •Evidence of rapidly deteriorating clinical status or disease-related complications that would limit safe participation (e.g., organ dysfunction or failure, hematologic complications), in the opinion of the investigator.
- •Prior or current evidence of clinically significant immune-mediated or inflammatory conditions (including pneumonitis) that, in the opinion of the investigator, would increase the risk of treatment with pembrolizumab.
- •Subjects who have entered or are participating in the optional treatment extension phase.
研究组 & 干预措施
350 mg dose of leronlimab in combination with trifluridine + tipiracil (TAS-102) + bevacizumab
Participants will receive leronlimab 350 mg in combination with trifluridine + tipiracil (TAS-102) and bevacizumab during the initial treatment period. Eligible participants who enter the Extension Treatment Period will continue the same treatment for up to an additional 52 weeks. Participants with documented disease progression during the initial treatment period who meet the applicable eligibility criteria may enter the optional open-label cohort and receive 700 mg leronlimab in combination with 200 mg pembrolizumab.
干预措施: 350 mg leronlimab (Drug)
350 mg dose of leronlimab in combination with trifluridine + tipiracil (TAS-102) + bevacizumab
Participants will receive leronlimab 350 mg in combination with trifluridine + tipiracil (TAS-102) and bevacizumab during the initial treatment period. Eligible participants who enter the Extension Treatment Period will continue the same treatment for up to an additional 52 weeks. Participants with documented disease progression during the initial treatment period who meet the applicable eligibility criteria may enter the optional open-label cohort and receive 700 mg leronlimab in combination with 200 mg pembrolizumab.
干预措施: 200 mg pembrolizumab (Drug)
700 mg dose of leronlimab in combination with trifluridine + tipiracil (TAS-102) + bevacizumab
Participants will receive leronlimab 700 mg in combination with trifluridine + tipiracil (TAS-102) and bevacizumab during the initial treatment period. Eligible participants who enter the Extension Treatment Period will continue the same treatment for up to an additional 52 weeks. Participants with documented disease progression during the initial treatment period who meet the applicable eligibility criteria may enter the optional open-label cohort and receive 700 mg leronlimab in combination with 200 mg pembrolizumab.
干预措施: 700 mg leronlimab (Drug)
700 mg dose of leronlimab in combination with trifluridine + tipiracil (TAS-102) + bevacizumab
Participants will receive leronlimab 700 mg in combination with trifluridine + tipiracil (TAS-102) and bevacizumab during the initial treatment period. Eligible participants who enter the Extension Treatment Period will continue the same treatment for up to an additional 52 weeks. Participants with documented disease progression during the initial treatment period who meet the applicable eligibility criteria may enter the optional open-label cohort and receive 700 mg leronlimab in combination with 200 mg pembrolizumab.
干预措施: 200 mg pembrolizumab (Drug)
结局指标
主要结局
To evaluate the efficacy of leronlimab in combination with trifluridine and tipiracil + bevacizumab in participants with CCR5+, refractory, MSS, mCRC.
时间窗: 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 CCR5+, 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 version 1.1.
The efficacy of leronlimab in combination with trifluridine and tipiracil + bevacizumab in participants with relapsed, refractory, MSS, mCRC.
时间窗: 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.
次要结局
- To assess the safety and tolerability of leronlimab when used in combination with trifluridine and tipiracil + bevacizumab in patients with CCR5+, refractory, MSS, mCRC.(From enrolment through end of treatment at 12 months.)
- To assess the duration of response of leronlimab in combination with trifluridine and tipiracil + bevacizumab in participants with CCR5+, MSS, mCRC(From enrolment through end of treatment at 12 months.)
- 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.)
- 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.)
- 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.)
- 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.)
- Assessment of individual progression free survival (PFS).(From first treatment through end of study (up to 160 weeks))
- Assessment of individual overall survival (OS).(From first treatment through end of study (up to 160 weeks).)