A Phase 1, Open-label, Multicenter, Dose-escalation and Cohort Expansion Study of OKN4395, a Triple Antagonist of EP2, EP4, and DP1 Prostanoid Receptors, as Monotherapy and in Combination With Pembrolizumab, in Patients With Advanced Solid Tumors
试验速览
- 阶段
- 1 期
- 状态
- 招募中
- 发起方
- 入组人数
- 146
- 试验地点
- 20
- 主要终点
- Incidence of DLTs in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab. (Phase 1a)
研究概览
简要总结
The purpose of this study is to investigate the study drug, OKN4395, administered alone and in combination with pembrolizumab.
The overall objectives of this study are to determine the safety and tolerability (degree to which side effects of a drug can be tolerated) of OKN4395 alone and in combination with pembrolizumab, OKN4395 and metabolites (broken-down substances) of OKN4395 levels in the blood, and antitumor activity of OKN4395 alone and in combination with pembrolizumab.
This study will be split into 2 parts. Part 1a will look at multiple doses of OKN4395 either alone (monotherapy) or with pembrolizumab (combination therapy) administered on day 1 of each 21-day cycle in patients with solid tumors until the participant has disease progression or discontinues for any reason. The dose of OKN4395 will be increased, after each group of 3 or more participants completes their first 3 weeks of treatment and their data is evaluated for safety, with a planned dose range from 10 mg twice a day to 450 mg twice a day through 13 dose levels. Part 1a also includes a parallel substudy (Substudy 1) consisting of at least 12 participants, aiming to test the effect of food and stomach acid on the levels of OKN4395 in the blood as well as its tolerability.
Part 1b will evaluate OKN4395 alone and in combination with pembrolizumab administered on day 1 of each 21-day cycle in patients with selected cancer types. Part 1b will comprise 4 cohorts: Cohort 1 in sarcoma (OKN4395 alone), Cohort 2 in non-small cell lung cancer (NSCLC), Cohort 3 in colorectal cancer, and Cohort 4 in gastric cancer (GC), with cohorts 2 to 4 in combination with pembrolizumab.
The overall study will enrol approximately 146 participants with up to 54 participants to receive OKN4395 alone and 12 participants to receive OKN4395 in combination with pembrolizumab in Part 1a, and 80 participants in Part 1b split: 20 on monotherapy and 60 on combination therapy.
The study will be conducted in the US, Australia, UK and in the EU.
研究设计
- 研究类型
- Interventional
- 分配方式
- Non 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
- •Histologically or cytologically confirmed disease, locally advanced or metastatic:
- •For Phase 1a:
- •Solid tumor with a COX2-associated immunosuppressive pathway, for which standard treatment options are not available, no longer effective, refused or not tolerated.
- •For Phase 1b:
- •For all cohorts, in the opinion of the investigator, all appropriate authorized treatment options should be exhausted
- •Cohort 1: Sarcoma (fibrous sarcoma [myxofibrosarcoma or solitary fibrous tumor], dedifferentiated liposarcoma, undifferentiated pleomorphic sarcoma or pleomorphic sarcoma, or leiomyosarcoma), that is either refractory to or progressing on standard of care, with no more than 3 prior lines of systemic therapy. Patients with a solitary fibrous tumor can be included in the study without prior treatment if, in the investigator's opinion, it is in the participant's best interest and no established standard of care exists or is available.
- •Cohort 2: NSCLC (squamous or adenomatous without EGFR/ALK mutations), with disease progression on a PD-(L)1 CPI regimen, and no more than 3 prior lines of systemic therapy. When known, PD-L1 status should be provided.
- •Cohort 3: CRC (Microsatellite stable or Microsatellite instability - low), and no more than 4 prior lines of systemic therapy.
- •Cohort 4: GC (gastric and gastro-esophageal junction adenocarcinoma), HER2-negative, planned to or currently receiving CPI monotherapy as maintenance of a first-line CPI + chemotherapy regimen, after chemotherapy cessation.
- •ECOG performance status of 0 or
- •Recovery from any medically relevant AE/irAE from previous treatment regimen (defined as recovery to Grade ≤1 level per CTCAE v 5.0 before Screening, or chronic, stable, Grade 2 AEs [not worsened to Grade >2 for >3 months prior to screening]).
- •One or more new or growing tumor lesions amenable to a safe biopsy (at baseline, a suitable archival specimen obtained when not undergoing treatment and within 1 year [Phase 1a], or within 90 days and after the last administration of the previous systemic therapy [Phase 1b] is suitable). In addition (where applicable) an archival tumor biopsy collected before the start of the first-line treatment in the metastatic setting is requested (but optional).
- •At least one target lesion measurable by RECIST 1.1 as noted by local investigators/radiologists.
- •The ability to swallow and retain OKN4395 as an oral medication without significant gastrointestinal abnormalities that might alter absorption.
- •The willingness and ability to comply with the evaluation, randomizations and requirements of the protocol. For Substudy 1, the ability to comply with the evaluation requirements includes the absence of any condition known to affect upper gastrointestinal motility, absorption, and pH.
- •Adequate hematologic, renal, and hepatic function (based on local laboratory assessments):
- •Hematological variables: absolute neutrophil counts ≥1.5 × 109 /L, platelet counts ≥75 × 109 /L, and hemoglobin ≥8 g/dL
- •Renal variables: creatinine clearance ≥ 60 mL/min1 by Du Bois & Du Bois formula
- •Hepatic variables: total serum bilirubin ≤1.5 × ULN, AST and ALT ≤3 × ULN, and ALP ≤2.5 × ULN; except for hyperbilirubinemia of Gilbert's syndrome (participants with Gilbert's syndrome can be included if total serum bilirubin ≤5× ULN and direct bilirubin ≤1.5 x ULN)
- •Serum albumin ≥30 g/L
排除标准
- •Except for the current regimen in Cohort 4, ongoing or recent anticancer therapy within the following timeframe prior to first dose of study drug:
- •Chemotherapy, ADCs, or other antibodies < 21 days
- •Immunotherapy or cellular therapy < 28 days
- •Radiation therapy (palliative radiation for bone pain <48 hours; stereotactic or small field brain irradiation <7 days; all other radiation therapy <14 days)
- •TKI or any other anticancer therapy < 5 half-lives or < 7 days, whichever is longer
- •Central nervous system metastasis (radiologically progressive, or clinically symptomatic, or requiring immunosuppressive therapies [including low dose steroids]).
- •Any active infection (bacterial, viral, fungal) requiring IV systemic therapy.
- •Unstable COPD defined as frequent or severe exacerbations per investigator discretion.
- •Known history of or active HBV (HBsAg reactive and/or HBV DNA detected) or HCV (HCV RNA detected) infection.
- •HIV infection with CD4 lymphocyte count <350 cells/μL at time of Screening, or failure to achieve and maintain virologic suppression defined as confirmed HIV RNA level < 50 or lower limit of detection by the local available assay at time of Screening and for at least 12 weeks prior to Screening.
- •Known history of bleeding disorders, INR ≥1.5 × ULN at screening (or INR and/or aPTT within therapeutic range if on anticoagulation therapy), or a history of gastrointestinal bleeding (inflammatory, ulcerative, or diverticular) within the last 2 years.
- •Known H. pylori infection without proof of eradication at least 2 months prior to screening.
- •Systemic treatment with any drug known to impact gastrointestinal pH within 7 days (PPIs) or 12 hours (H2 antagonists) of first dose of OKN4395 (unless adapted after Substudy 1). Where said treatments have been used for more than 2 weeks prior to discontinuation, discontinuation should occur at least 21 days before first dose of OKN
- •Acute treatment with any systemic steroid therapy (>10 mg prednisone equivalent), or any corticosteroid medication within 14 days of first dose of OKN4395 for any condition.
- •For participants planned to receive combination therapy: Ongoing and history of active autoimmune disease that has required systemic treatment in the past 2 years (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Any replacement therapy (i.e. thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed. Participants with hyperthyroidism or hypothyroidism but that are stable on hormone replacement are also allowed.
- •Systemic treatment with NSAIDs, COX2 inhibitors, or synthetic prostaglandins within 5 half-lives prior to the first dose of OKN4395 (acetylsalicylic acid ≤ 160 mg/day, or 325 mg ≤ 3 times/week is permitted).
- •Systemic treatment with strong inhibitors/inducers of CYP and UGT enzymes within 14 days of first dose of OKN
- •QTcF interval of > 450 ms based on mean of the central triplicate readings.
- •Known hypersensitivity to any excipients of the OKN4395 formulation or pembrolizumab (for combination cohorts).
- •Pregnant or lactating women. Women of childbearing potential must have a negative serum pregnancy test at screening and have a negative a urine dipstick pregnancy test prior to the initiation of study treatment (can be done on C1-D1 visit).
- •Evidence of any other active malignancy requiring systemic therapy within the 2 years prior to Screening. (Exceptions: non-melanoma skin cancer, in situ melanoma, in situ cervical cancer, ductal carcinoma in situ of the breast, or localized and presumed cured prostate cancer; participants on long-term anti-hormonal therapy for a prior malignancy are allowed if the malignancy has not been active within the prior 2 years).
- •History or current evidence of any condition, surgical or medical therapy, or laboratory abnormalities that might confound the results of the study, make study drug administration hazardous, interfere with the participant's involvement for the full duration of the study, or make it difficult to monitor AEs such that, in the opinion of the treating physician, it is not in the best interest of the participant to participate
研究组 & 干预措施
Combination Dose Confirmation Phase (Phase 1a)
The Combination Dose Confirmation Phase will include increasing or decreasing doses of OKN4395 in combination with pembrolizumab in patients with solid tumors with a COX2-associated immunosuppressive pathway. The first dose level used will be 1 level below the identified OBD/MTD for monotherapy. Subsequent dose levels tested will either be increased or decreased in response to observed toxicity.
干预措施: OKN4395 (Drug)
Monotherapy Dose Escalation Phase (Phase 1a)
The Monotherapy Escalation Phase will include increasing doses of OKN4395 alone in patients with solid tumors with a COX2-associated immunosuppressive pathway.
干预措施: OKN4395 (Drug)
Combination Dose Confirmation Phase (Phase 1a)
The Combination Dose Confirmation Phase will include increasing or decreasing doses of OKN4395 in combination with pembrolizumab in patients with solid tumors with a COX2-associated immunosuppressive pathway. The first dose level used will be 1 level below the identified OBD/MTD for monotherapy. Subsequent dose levels tested will either be increased or decreased in response to observed toxicity.
干预措施: Pembrolizumab (Combination Product)
结局指标
主要结局
Incidence of DLTs in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab. (Phase 1a)
时间窗: From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months
DLTs = dose-limiting toxicities
Incidence and severity of TEAEs in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1a)
时间窗: From enrolment of the first participant to the end of Phase 1a; up to 27 months
TEAEs = treatment-emergent adverse events
Incidence and severity of SAEs in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1a)
时间窗: From enrolment of the first participant to the end of Phase 1a; up to 27 months
SAEs = serious adverse events
Incidence of dose interruptions, dose reductions, and dose intensities in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1a)
时间窗: From enrolment of the first participant to the end of Phase 1a; up to 27 months
Incidence and severity of clinically relevant ECG abnormalities in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1a)
时间窗: From enrolment of the first participant to the end of Phase 1a; up to 27 months
ECG = electrocardiogram
Incidence and severity of laboratory abnormalities in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1a)
时间窗: From enrolment of the first participant to the end of Phase 1a; up to 27 months
Graded where appropriate with the CTCAE v5.0.
Incidence and severity of clinically relevant changes in vital signs in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1a)
时间窗: From enrolment of the first participant to the end of Phase 1a; up to 27 months
To assess the overall response rate in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1b)
时间窗: From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b
次要结局
- To assess the overall response rate in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1a)(From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months)
- To assess the disease control rate at >=12 weeks in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1a)(From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months)
- To assess the duration of response in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1a)(From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months)
- To assess the progression-free survival in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1a)(From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months)
- To assess the time to treatment failure in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1a)(From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months)
- To assess the overall survival rate at 24 weeks in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1a)(From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months)
- To characterize the accumulation index (pharmacokinetics) of OKN4395 and its AG metabolite. (Phase 1a)(From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months)
- To characterize the maximum plasma concentration (pharmacokinetics) of OKN4395 and its AG metabolite. (Phase 1a)(From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months)
- To characterize the area under the curve (pharmacokinetics) of OKN4395 and its AG metabolite. (Phase 1a)(From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months)
- To characterize the terminal half life (pharmacokinetics) of OKN4395 and its AG metabolite. (Phase 1a)(From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months)
- To characterize the clearance (pharmacokinetics) of OKN4395 and its AG metabolite. (Phase 1a)(From enrolment of the first participant until the end of Phase 1a or until the DLT threshold is reached; up to 27 months)
- To assess the disease control rate at >=12 weeks in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- To assess the duration of response in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- To assess the progression-free survival in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- To assess the time to treatment failure in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- To assess the overall survival rate at 24 weeks in participants treated with OKN4395 as monotherapy and in combination with pembrolizumab in selected cancer types. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- Incidence and severity of TEAEs in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- Incidence and severity of SAEs in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- Incidence of dose interruptions, dose reductions, and dose intensities in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- To characterize the maximum plasma concentration (pharmacokinetics) of OKN4395 and its AG metabolite. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- Incidence and severity of clinically relevant ECG abnormalities in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- Incidence and severity of laboratory abnormalities in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- Incidence and severity of clinically relevant changes in vital signs in participants treated with OKN4395 as a monotherapy and in combination with pembrolizumab in solid tumors. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- To characterize the area under the curve (pharmacokinetics) of OKN4395 and its AG metabolite. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- To characterize the terminal half life (pharmacokinetics) of OKN4395 and its AG metabolite. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- To characterize the clearance (pharmacokinetics) of OKN4395 and its AG metabolite. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)
- To characterize the accumulation index (pharmacokinetics) of OKN4395 and its AG metabolite. (Phase 1b)(From enrolment of first participant in Phase 1b until 24 weeks after the last participant is enrolled in Phase 1b; up to 12 months from beginning of Phase 1b)