Calaspargase Pegol-Mnkl and Cobimetinib for the Treatment of Locally Advanced or Metastatic Pancreatic Cancer

Study Overview
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Brief Summary
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This phase I trial tests the safety, side effects, and best dose of calaspargase pegol-mknl in combination with cobimetinib in treating patients with pancreatic cancer that has spread to nearby tissue or lymph nodes (locally advanced) or has spread to other places in the body (metastatic). Cobimetinib attacks a protein called MEK that has been known to stimulate cells that promote the growth of cancer cells in the body. Calaspargase pegol-mknl is an enzyme that converts the amino acid L-asparagine into aspartic acid and ammonia. Many types of cancer cell rely on the amino acid L-asparagine, and depleting this amino acid with calaspargase pegol-mknl starves cancer cells of this nutrient. Attacking the MEK protein with cobimetinib is thought to further prevent cancer cells from using this amino acid, causing them to die. Giving calaspargase pegol-mknl in combination with cobimetinib may help control the disease in patients with pancreatic cancer.

Detailed Description
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PRIMARY OBJECTIVE: I. To determine the maximum tolerated dose (MTD) of calaspargase pegol-mknl in combination with cobimetinib. SECONDARY OBJECTIVES: I. To assess the safety of calaspargase pegol-mknl in combination with cobimetinib. II. To assess preliminary response to treatment with calaspargase pegol-mknl and cobimetinib. III. To monitor levels of plasma asparaginase. EXPLORATORY OBJECTIVE: I. To evaluate therapy induced changes in the tumor and tumor ecosystem. OUTLINE: This is a dose-escalation study. Patients receive calaspargase pegol-mknl intravenously (IV) over 1 hour on day 1 and cobimetinib orally (PO) once daily (QD) on days 1-14. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients also undergo a biopsy 14 days prior to starting therapy and on day 14 of cycle 2. After completion of study intervention, patients are followed up at 3 and 6 months.

Official Title
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A Phase I, Open-Label, Dose Finding Study of Calaspargase Pegol-Mnkl in Combination With Cobimetinib in Locally-Advanced or Metastatic Pancreatic Cancer

Conditions
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Locally Advanced Pancreatic Adenocarcinoma, Metastatic Pancreatic Adenocarcinoma, Stage II Pancreatic Cancer AJCC v8, Stage IIA Pancreatic Cancer AJCC v8, Stage IIB Pancreatic Cancer AJCC v8, Stage III Pancreatic Cancer AJCC v8, Stage IV Pancreatic Cancer AJCC v8

Intervention / Treatment
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* Procedure: Biopsy
* Drug: Calaspargase Pegol-mknl
* Drug: Cobimetinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participant must provide written informed consent before any study-specific procedures or interventions are performed Participants are >= 18 years old at the time of informed consent. Both men and women of all races and ethnic groups will be included Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 Histologically or cytologically-proven adenocarcinoma of the exocrine pancreas with locally advanced or metastatic disease Must have measurable disease as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version (v)1.1 Must have at least one disease lesion that is amenable to biopsy procedures performed per institutional standards Must have progressed on, been intolerant to, or refused systemic therapy that is consistent with institutional standards (e.g., Gemcitabine-based, or fluorouracil, irinotecan, leucovorin and oxaliplatin [FOLFORINOX]) Must not have received any systemic therapy or other investigational agents within 30 days or 5 half-lives (whichever is longer) from first dose of study therapy This requirement is waived for patients receiving cobimetinib or other investigational agent(s) as part of participation in NCT04005690, provided that all prior drug-related toxicities have resolved to Grade ≤ 1 prior to initiating study intervention Hemoglobin: >= 9.0 g/dL with no blood transfusion within 14 days of starting treatment White blood cells (WBC): > 3 x 10^9/L Absolute neutrophil count (ANC): >= 1.5 x 10^9/L (> 1500 per mm^3) Platelet count: >= 100 x 10^9/L (> 100,000 per mm^3) Creatinine =< 1.5 x upper limit of normal (ULN), or measured or calculated creatinine clearance >= 60 mL/min/1.73 m^2 for participants with creatinine levels > 1 x institutional (ULN) Serum bilirubin: =< 1.5 x institutional ULN Aspartate aminotransferase (AST)/alanine aminotransferase (ALT): =< 2.5 x ULN Participants of childbearing potential (POCBP) must agree to abstain from sexual intercourse or use effective non-hormonal methods of contraception starting with the first dose of study therapy through 90 days after the last dose of study therapy (because calaspargase pegol can render hormonal contraceptives ineffective) POCBP may participate provided they have a negative serum pregnancy test at screening and a negative serum OR urine pregnancy test within 7 days of starting treatment Exclusion Criteria: Concomitant use of other anti-cancer therapy (chemotherapy, immunotherapy, hormonal therapy (hormone replacement therapy is acceptable), radiotherapy (except for palliative), biological therapy or other novel agent) or live virus and live bacterial vaccines while receiving study medication Prior treatment with an L-asparaginase therapy Known severe hypersensitivity to calaspargase pegol-mknl (or equivalent) or to cobimetinib (or equivalent), or to any excipient of these medicinal products, or history of allergic reactions attributed to compounds of similar chemical or biologic composition to calaspargase pego-mknl or cobimetinib Use of known strong CYP3A inhibitors (e.g., itraconazole, telithromycin, clarithromycin, protease inhibitors boosted with ritonavir or cobicistat, indinavir, saquinavir, nelfinavir, boceprevir, telaprevir), known strong CYP3A inducers (e.g., phenobarbital, enzalutamide, phenytoin, rifampicin, rifabutin, rifapentine, carbamazepine, nevirapine and St John's Wort) or moderate CYP3A inducers (e.g., bosentan, efavirenz, modafinil) within 7 days of prior to initiating study treatment or on going requirement for these medications Uncontrolled serious thrombosis Uncontrolled severe or symptomatic coagulopathy; exclude if: Prothrombin time (PT) >= 1.5 x ULN, or International normalized ratio (INR) >= 1.5 x ULN, or Fibrinogen =< 0.66 x LLN Known history of chronic pancreatitis or recurrent acute pancreatitis, or at time of screening evidence of acute pancreatitis, defined by at least two of the following: Clinical symptoms of upper abdominal pain Serum amylase or lipase that is >= 3 x ULN Imaging evidence (computed tomography [CT], magnetic resonance imaging [MRI], ultrasonography) Significant cardiac disease within 6 months prior to start of study treatment, including any of the following: New York Heart Association class III or IV, Congestive heart failure, acute coronary syndrome, and/or stroke, or Left ventricular ejection fraction (LVEF) < 40% by echocardiogram (ECHO) or multigated acquisition (MUGA) scan obtained within 28 days prior to start of study treatment Known risk factors for ocular toxicity, consisting of any of the following: History of serous retinopathy History of retinal vein occlusion (RVO) Evidence of ongoing serous retinopathy or RVO at screening Uncontrolled hypertension, or hypertension that cannot otherwise be clinically managed before initiating study therapy Participant is known to have dysphagia, short-gut syndrome, gastroparesis, or other conditions that limit the ingestion or gastrointestinal absorption of drugs administered orally Participant has active uncontrolled systemic fungal, bacterial, or viral infection (defined as ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics, antiviral therapy, and/or other treatment) Participant has corrected QT (QTc) interval (i.e., Fridericia's correction [QTcF]) >= 450 ms or other factors that increase the risk of QT prolongation or arrhythmic events (e.g., heart failure, hypokalemia, family history of long QT interval syndrome) at screening Psychiatric illness/social situations that would limit compliance with study requirements Any concurrent severe and/or uncontrolled medical condition (e.g. uncontrolled diabetes, infection, hypertension, etc.) Participant is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through 90 days after the last dose of trial treatment Judgment by the investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions and requirements

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Treatment (calaspargase pegol-mknl, cobimetinib)<br>Patients receive calaspargase pegol-mknl IV over 1 hour on day 1 and cobimetinib PO QD on days 1-14. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. | Procedure: Biopsy<br>* Undergo biopsy<br>* Other names: Bx;Drug: Calaspargase Pegol-mknl<br>* Given IV<br>* Other names: Succinimidyl Carbonate Monomethoxypolyethylene Glycol E. coli L-Asparaginase;Drug: Cobimetinib<br>* Given PO<br>* Other names: XL518;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of dose-limiting toxicities (DLTs) | Defined as any treatment-related grade >= 3 non-hematological or hematological adverse events. The incidence of DLT at each dose level will be summarized using the proportion and exact binomial confidence interval. Dose-limiting toxicities will specifically be reported for the DLT evaluation period using the maximum tolerated dose (MTD)-evaluable population. The MTD will be identified using isotonic regression. | Up to cycle 2 day 21 (1 cycle = 21 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of treatment-emergent adverse events (AEs) and serious AEs | Evaluated by Common Terminology Criteria for Adverse Events version 5.0. | Up to 30 days after last dose of study intervention | 
| Objective response rate (ORR) | Evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. Overall response will be summarized descriptively. ORR will be estimated with 95% confidence interval. The confidence interval will be calculated based on the exact method for binomial distributions. | Up to 6 months after initiating study intervention | 
| Disease control rate (DCR) | Evaluated using RECIST version 1.1. An estimate of DCR will be measured and reported with 95% exact confidence interval. Participants who achieve a complete response, partial response, or stable disease for at least 6 months on the current protocol will be qualified as deriving benefit from therapy and will count towards the DCR measurement. | Up to 6 months after initiating study intervention | 
| Mean plasma asparaginase activity | Will be reported with 95% confidence interval. | Up to 6 cycles from initiating study intervention (1 cycle = 21 days) |