Phase Ib Study of Cabozantinib in Combination With Lu-177 DOTATATE Peptide Receptor Radionuclide Therapy (PRRT) in Patients With Progressive, Previously Treated Somatostatin Receptor 2 (SSTR2) Positive Neuroendocrine Tumors (NETs)
概览
- 阶段
- 1 期
- 干预措施
- Cabozantinib
- 疾病 / 适应症
- Neuroendocrine Tumors
- 发起方
- Providence Health & Services
- 入组人数
- 6
- 试验地点
- 2
- 主要终点
- Establish the maximal tolerated dose of cabozantinib in combination with Lu-177 dotatae at a standard dose of 7.4 GBg in four 8-week cycles followed by continuation of cabozantinib.
- 状态
- 进行中（未招募）
- 最后更新
- 19天前
概览
简要总结
The phase I objective of this study is to establish the maximal tolerated dose (MTD) of cabozantinib in 20 mg, 40 mg and 60 mg dose escalation cohorts in combination with Lu-177 dotatate at a standard dose of 7.4 GBq in four (4) 8-week cycles followed by continuation cabozantinib.
详细描述
Patients will be treated four (4) cycles of combination cabozantinib with Lu-177 DOTATATE followed by maintenance cabozantinib. Cycles 1-4 combination cabozantinib with Lu-177 DOTATATE is given in 8-week cycles, with cabozantinib initiated on day 1 and Lu-177 DOTATATE given on day 14. Cabozantinib dosing is escalated during cycles 1-4 in the following manner: dose cohort 1 patients receive cabozantinib 20 mg daily, cohort 2 receive 40mg qod alternating with 20 mg qod, cohort 3 receive 40 mg qd, dose cohort 4 receive 60 mg qod alternating with 40 mg qod, and dose cohort 5 receive 60 mg qd. In all cohorts, during cycle 5 and beyond, single-agent maintenance cabozantinib is given in 4-week cycles in a qd dosing scheduling as follows: 20 mg qd cohort 1; 40 mg qd cohort 2; 40 mg qd cohort 3; 60 mg qd cohort 4; 60 mg qd cohort 5, until disease progression.
研究者
入排标准
入选标准
- •Patients with unresectable, progressive, histologically well-differentiated neuroendocrine tumors of the fore-, mid-, or hindgut, including pancreas, or those with an unknown primary with target lesions overexpressing somatostatin receptors (Krenning 2, 3 or 4) on a SSTR PET.
- •Patients must have previously received one or more lines of systemic therapy including somatostatin analogue therapy.
- •Prior PRRT therapy is permitted up to a maximum of 4 standard doses. Enrollment of R-PRRT patients is permitted after initially 3 PRRT-naïve patients have been enrolled on protocol and if the minimum progression free survival (PFS) with initial PRRT therapy was ≥ 18 months from day 1, cycle 1 of PRRT to progression.
- •Recovery to baseline or ≤ Grade 1 (CTCAE v5.0) from toxicities related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
- •Minimum 18 years or older.
- •Adequate organ and marrow function, based upon meeting all of the following laboratory criteria within 14 days before first dose of study treatment:
- •Absolute neutrophil count (ANC) ≥ 1500/µL without granulocyte colony-stimulating factor support.
- •White blood cell count ≥ 2500/µL.
- •Platelets ≥ 100,000/µL without transfusion.
- •Hemoglobin ≥ 9 g/dL (≥ 90 g/L).
排除标准
- •Prior therapy with cabozantinib.
- •Tumors with poorly differentiated or small cell histology.
- •Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
- •Receipt of any type of cytotoxic, biologic or other systemic anticancer therapy (including investigational) within 4 weeks before first dose of study treatment.
- •Radiation therapy for bone metastasis within 2 weeks or any other radiation therapy within 4 weeks before first dose of study treatment. Systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Participants with clinically relevant ongoing complications from prior radiation therapy are not eligible.
- •Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to first dose of study treatment after major surgery (e.g., removal or biopsy of brain metastasis). Participants must have complete wound healing from major surgery or minor surgery before first dose of study treatment. Eligible participants must be neurologically asymptomatic and without corticosteroid treatment at the time of first dose of study treatment.
- •Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:
- •Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH).
- •Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who are on a stable dose of the anticoagulant for at least 1 week before first dose of study treatment without clinically significant hemorrhagic complications from the anticoagulation regimen or the tumor.
- •The participant has uncontrolled, significant intercurrent or recent illness including, but not limited to, the following conditions:
研究组 & 干预措施
Cohort 1
Cabozantinib 20 mg daily with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 20 mg qd.
干预措施: Cabozantinib
Cohort 1
Cabozantinib 20 mg daily with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 20 mg qd.
干预措施: Lu-177
Cohort 2
Cabozantinib 40 mg qod alternating with 20 mg qod with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 40 mg qd.
干预措施: Cabozantinib
Cohort 2
Cabozantinib 40 mg qod alternating with 20 mg qod with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 40 mg qd.
干预措施: Lu-177
Cohort 3
Cabozantinib 40 mg qd with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 40 mg qd.
干预措施: Cabozantinib
Cohort 3
Cabozantinib 40 mg qd with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 40 mg qd.
干预措施: Lu-177
Cohort 4
Cabozantinib 60 mg qod alternating with 40 mg qod with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 60 mg qd.
干预措施: Cabozantinib
Cohort 4
Cabozantinib 60 mg qod alternating with 40 mg qod with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 60 mg qd.
干预措施: Lu-177
Cohort 5
Cabozantinib 60 mg qd with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 60 mg qd until disease progression.
干预措施: Cabozantinib
Cohort 5
Cabozantinib 60 mg qd with Lu-177 DOTATE administration IV. For cycles 5+, single-agent maintenance of cabozantinib is given at 60 mg qd until disease progression.
干预措施: Lu-177
结局指标
主要结局
Establish the maximal tolerated dose of cabozantinib in combination with Lu-177 dotatae at a standard dose of 7.4 GBg in four 8-week cycles followed by continuation of cabozantinib.
时间窗: Up to 2 years
The phase I objective of this study is to establish the maximal tolerated dose (MTD) of cabozantinib in 20 mg, 40 mg and 60 mg dose escalation cohorts in combination with Lu-177 dotatate at a standard dose of 7.4 GBq in four (4) 8-week cycles followed by continuation cabozantinib. Due to overlapping toxicities of cabozantinib and Lu-177 dotatate and to allow more incremental dose escalation of cabozantinib, alternating day dosing of 40mg/20mg and 60mg/40mg cohorts are incorporated into the schema. This is expected to reduce the risk of overlapping toxicities while still achieving radio-sensitizing anti-angiogenic, multi-targeted therapy in combination with the beta-emitting radiation from lutetium 177 synergistic due to the prolonged half-life of cabozantinib.
次要结局
- Establish objective response rate as measured by RECIST 1.1(Up to 2 years post study completion)