Calaspargase Pegol-Mnkl And Cobimetinib For The Treatment Of Locally Advanced Or Metastatic Pancreatic Cancer

Study Overview

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

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.

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.

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

PROCEDURE: Biopsy
DRUG: Calaspargase Pegol-mknl
DRUG: Cobimetinib

STUDY00022141
NCI-2021-09061 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
STUDY00022141 (OTHER Identifier) (OTHER: OHSU Knight Cancer Institute)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2021-08-30	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2024-10-24
First Submitted that Met QC Criteria 2021-08-30	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2024-10-28
First Posted (ACTUAL) 2021-09-05	Results First Posted N/A	Last Verified 2024-10

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Treatment (calaspargase pegol-mknl, cobimetinib) 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 Undergo biopsy DRUG: Calaspargase Pegol-mknl Given IV DRUG: Cobimetinib Given PO

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Treatment (calaspargase pegol-mknl, cobimetinib)

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

Undergo biopsy

DRUG: Calaspargase Pegol-mknl

Given IV

DRUG: Cobimetinib

Given PO

Primary Outcome Measures	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	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)

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Oregon Health and Science University
Genentech, Inc.
Servier Pharmaceuticals, LLC

Investigators

PRINCIPAL_INVESTIGATOR: Charles D Lopez, OHSU Knight Cancer Institute

Publications

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