A Phase 1/Randomized Phase 2 Study to Evaluate LY2603618 in Combination With Pemetrexed and Cisplatin in Patients With Stage IV Non-small Cell Lung Cancer
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 76
- 试验地点
- 1
- 主要终点
- Phase 1: Recommended Phase 2 Dose of LY2603618
研究概览
简要总结
LY2603618 is a selective inhibitor of the deoxyribonucleic acid (DNA) damage checkpoint kinase 1 (CHK1). It was being developed as a chemotherapeutic-enhancing agent in the treatment of cancer. Phase 1 studies have shown the feasibility of combining LY2603618 with either gemcitabine or pemetrexed. The objective of this study was to find the dose of LY2603618 that can be safely combined with standard doses of pemetrexed and cisplatin and to test if this triplet offered a significant improvement in progression-free survival (PFS) in participants with Stage IV nonsquamous non-small cell lung cancer (NSCLC) in the first-line of palliative treatment.
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
- •Phase 1 portion:
- •Participants with a cytologic or histologic diagnosis of nonsquamous NSCLC that is classified as Stage IV according to the 7th edition of the American Joint Committee on Cancer (AJCC) classification and for whom the combination of pemetrexed and cisplatin is deemed to be appropriate
- •Participants with histologic or cytologic diagnosis of malignant mesothelioma that is unresectable
- •Participants with histologic or cytologic diagnoses of advanced or metastatic solid tumors who are not candidates for any standard therapy and for whom the combination with pemetrexed and cisplatin is deemed to be appropriate
- •Phase 2 portion:
- •Have a histological diagnosis of NSCLC other than predominantly squamous cell histology that is classified as Stage IV according to the 7th edition of the AJCC classification
- •Eligible for a first line of palliative treatment with a platinum doublet
- •Have archived or fresh tumor tissue (not cytology)
- •Phase 1 participants can have measurable or nonmeasurable disease. Phase 2 participants must have at least 1 measurable lesion according to Investigational New Drug (Response Evaluation Criteria in Solid Tumors [RECIST], v1.1) definitions. Tumor lesions located in a previously irradiated area can be considered measurable if they are new or if have shown unequivocal progression.
- •Have a performance status ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale
- •Have adequate hematologic, hepatic, and renal organ function
- •Prior radiation therapy for treatment of cancer is allowed to <25% of the bone marrow, and participants must have recovered from the acute toxic effects of their treatment prior to study enrollment. Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 4 weeks before study entry
- •For women: Must be surgically sterile, postmenopausal, or compliant with a highly reliable contraceptive method (failure rate <1%) during and for 6 months after the treatment period; must have a negative serum or urine pregnancy test within 7 days before study enrollment and must not be breast-feeding. For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 6 months after the treatment period
排除标准
- •Have serious preexisting medical conditions or serious concomitant systemic disorders that would compromise the safety of the participant or his/her ability to complete the study, at the discretion of the investigator (for example, unstable angina pectoris or uncontrolled diabetes mellitus). Special attention should be paid to kidney and heart conditions that may be worsened with cisplatin treatment or hydration
- •Have central nervous system (CNS) metastases (unless the participant has completed successful local therapy for CNS metastases and has been off corticosteroids for at least 4 weeks before starting study therapy). A screening computed tomography scan or magnetic resonance imaging before enrollment in the absence of a clinical suspicion of brain metastases is not required.
- •Have current active infection that would, in the opinion of the investigator, compromise the participant's ability to tolerate therapy
- •Have known allergy to pemetrexed, cisplatin, LY2603618, or any ingredient of pemetrexed, cisplatin, or LY2603618
- •Have clinically significant (by physical exam) third-space fluid collections; for example, ascites or pleural effusions that cannot be controlled by drainage or other procedures prior to study entry
- •Participants taking non-steroidal anti-inflammatory drugs who cannot interrupt the treatment appropriately according to the guidelines
- •Have received a recent yellow-fever vaccination (within 28 days of enrollment) or are receiving concurrent yellow-fever vaccination
- •Phase 1 portion:
- •Have received more than 2 previous lines of chemotherapy for the advanced/metastatic disease
- •Have received more than 6 cycles of therapy containing an alkylating agent
研究组 & 干预措施
Phase 1: LY2603618 130 to 275 mg
Cycle 1-2 (21-day cycle):
Day 1: pemetrexed 500 milligrams per meter square (mg/m^2) + cisplatin 75 mg/m^2
Day 2: LY2603618 at 130-275 milligrams (mg)
After 2 cycles, participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
干预措施: Pemetrexed (Drug)
Phase 1: LY2603618 130 to 275 mg
Cycle 1-2 (21-day cycle):
Day 1: pemetrexed 500 milligrams per meter square (mg/m^2) + cisplatin 75 mg/m^2
Day 2: LY2603618 at 130-275 milligrams (mg)
After 2 cycles, participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
干预措施: Cisplatin (Drug)
Phase 1: LY2603618 130 to 275 mg
Cycle 1-2 (21-day cycle):
Day 1: pemetrexed 500 milligrams per meter square (mg/m^2) + cisplatin 75 mg/m^2
Day 2: LY2603618 at 130-275 milligrams (mg)
After 2 cycles, participants may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
干预措施: LY2603618 (Drug)
Phase 2: Pemetrexed + Cisplatin + LY2603618
Cycles 1-4 (21-day cycle):
Before 25 Oct 2012:
Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2
Day 2: LY2603618 dose from phase 1 portion of trial
After 25 Oct 2012:
Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2
After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
Maintenance Therapy Experimental Arm (every 21 days):
Before 25 Oct 2012:
Day 1: pemetrexed 500 mg/m^2
Day 2: LY2603618 dose determined from phase 1
After 25 Oct 2012:
Day 1: pemetrexed 500 mg/m^2
If, as of 25 Oct 2012, participant was in maintenance therapy and randomized to the experimental arm, the participant is eligible to continue with pemetrexed (Day 1)/LY2603618 (Day 2) therapy if the investigator deems it is in the best interest of the participant and the participant consents.
干预措施: Pemetrexed (Drug)
Phase 2: Pemetrexed + Cisplatin + LY2603618
Cycles 1-4 (21-day cycle):
Before 25 Oct 2012:
Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2
Day 2: LY2603618 dose from phase 1 portion of trial
After 25 Oct 2012:
Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2
After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
Maintenance Therapy Experimental Arm (every 21 days):
Before 25 Oct 2012:
Day 1: pemetrexed 500 mg/m^2
Day 2: LY2603618 dose determined from phase 1
After 25 Oct 2012:
Day 1: pemetrexed 500 mg/m^2
If, as of 25 Oct 2012, participant was in maintenance therapy and randomized to the experimental arm, the participant is eligible to continue with pemetrexed (Day 1)/LY2603618 (Day 2) therapy if the investigator deems it is in the best interest of the participant and the participant consents.
干预措施: Cisplatin (Drug)
Phase 2: Pemetrexed + Cisplatin + LY2603618
Cycles 1-4 (21-day cycle):
Before 25 Oct 2012:
Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2
Day 2: LY2603618 dose from phase 1 portion of trial
After 25 Oct 2012:
Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2
After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
Maintenance Therapy Experimental Arm (every 21 days):
Before 25 Oct 2012:
Day 1: pemetrexed 500 mg/m^2
Day 2: LY2603618 dose determined from phase 1
After 25 Oct 2012:
Day 1: pemetrexed 500 mg/m^2
If, as of 25 Oct 2012, participant was in maintenance therapy and randomized to the experimental arm, the participant is eligible to continue with pemetrexed (Day 1)/LY2603618 (Day 2) therapy if the investigator deems it is in the best interest of the participant and the participant consents.
干预措施: LY2603618 (Drug)
Phase 2: Pemetrexed + Cisplatin
Cycle 1-4 (21-day cycle):
Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2
After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
Maintenance Therapy Comparator Arm: Phase 2 (every 21 days):
Day 1: pemetrexed 500 mg/m^2
干预措施: Pemetrexed (Drug)
Phase 2: Pemetrexed + Cisplatin
Cycle 1-4 (21-day cycle):
Day 1: pemetrexed 500 mg/m^2 + cisplatin 75 mg/m^2
After 4 cycles, participants may continue on maintenance therapy until disease progression, unacceptable toxicity, or other withdrawal criterion is met.
Maintenance Therapy Comparator Arm: Phase 2 (every 21 days):
Day 1: pemetrexed 500 mg/m^2
干预措施: Cisplatin (Drug)
结局指标
主要结局
Phase 1: Recommended Phase 2 Dose of LY2603618
时间窗: Time of first dose to last dose
The recommended Phase 2 dose for LY2603618 when administered approximately 24 hours after pemetrexed and cisplatin was based on the maximum tolerated dose (MTD) and achievement of predefined LY2603618 plasma systemic exposures targets (area under the LY2603618 plasma concentration versus time curve from time zero to infinity \[AUC(0-∞)\] \>21,000 nanogram\*hour/milliliter \[ng\*h/mL\] and maximum LY2603618 plasma concentration \[Cmax\] \>2000 nanograms/milliliter \[ng/mL\]).
Phase 2: Progression-Free Survival Time
时间窗: Randomization up to first date of PD or death from any cause (up to 6 months after the last participant entered treatment)
Progression-free survival (PFS) time is defined as the time from the date of randomization to the first date of documented objective progressive disease (PD) or death from any cause. For participants who were not known to have had objective PD as of the data inclusion cut-off date for a particular analysis, PFS was censored at the date of the last objective progression-free disease assessments. For participants who took any subsequent systemic anticancer therapy prior to progression, PFS was censored at the date of the last objective progression-free disease assessment prior to the start date of any subsequent systemic anticancer therapy. PFS time was summarized using Kaplan-Meier estimates.
次要结局
- Phase 1: Pharmacokinetic: Cmax (Pemetrexed and Cisplatin)(Pemetrexed: Cycle 1/Day 1 - immediately prior to end of pemetrexed infusion and 1, 2, 6 and 24 hours postdose. Cisplatin: Cycle 1/Day 1 - immediately prior to end of cisplatin infusion and 0.5, 1, 2, 6, 24, 72, 96, and 168 hours postdose.)
- Phase 2: Proportion of Participants Receiving Maintenance Therapy(Cycle 5)
- Phase 1: Pharmacokinetic: AUC (Pemetrexed and Cisplatin)(Pemetrexed: Cycle 1/Day 1 - immediately prior to end of pemetrexed infusion and 1, 2, 6 and 24 hours postdose. Cisplatin: Cycle 1/Day 1 - immediately prior to end of cisplatin infusion and 0.5, 1, 2, 6, 24, 72, 96, and 168 hours postdose.)
- Phase 2: Overall Survival(Randomization to the date of death from any cause through the time of study discontinuation (approximately 12 months after last participant was randomized))
- Phase 2: Change in Tumor Size(Baseline, end of Cycle 2)
- Phase 1: Pharmacokinetic: Area Under the Plasma Concentration Versus Time Curve (AUC) (LY2603618)(Cycle 1/Day 2 - immediately prior to end of LY2603618 infusion and 1, 3, 6, 24, 48, 72, and 144 hours postdose; Cycle 2/Day 2 - predose, immediately prior to end of LY2603618 infusion, and 1, 3, 6, 24, 48, 72, and 144 hours postdose)
- Phase 2: Change From Baseline to Long-term Follow up in Lung Cancer Symptom Scale (LCSS)(Randomization to the end of study (approximately 12 months after the last participant entered treatment))
- Phase 1: Pharmacokinetic: Maximum Plasma Concentration (Cmax) (LY2603618)(Cycle 1/Day 2 - immediately prior to end of LY2603618 infusion, and 1, 3, 6, 24, 48, 72, and 144 hours postdose; Cycle 2/Day 2 - predose, immediately prior to end of LY2603618 infusion, and 1, 3, 6, 24, 48, 72, and 144 hours postdose)
- Phase 2: Pharmacokinetic: AUC (LY2603618)(Cycle 1/Day 2 - predose, immediately prior to the end of the LY2603618 infusion, and 2-6, 24-48, and 72-96 hours postdose)
- Phase 2: Overall Tumor Response Rate: Percentage of Participants Who Achieved a Confirmed Best Response of Completed Response (CR) or Partial Response (PR)(Randomization until date of disease progression (up to 6 months after the last participant was randomized))
- Phase 2: Pharmacokinetic: Cmax (LY2603618)(Cycle 1/Day 2 - predose, immediately prior to the end of the LY2603618 infusion, and 2-6, 24-48, and 72-96 hours postdose)
- Phase 1: Document Any Antitumor Activity Per Radiological Scans and/or Tumor Markers(Baseline through end of Phase 1)
- Phase 2: Clinical Benefit Rate: Percentage of Participant Who Achieved a Response of Stable Disease (SD), Partial Response (PR), or Complete Response (CR)(Randomization until date of disease progression or death (up to 6 months after the last participant was randomized))