Clinical trial NCT03918278: A Study of MK-0482 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-0482-001)
Official title: A Phase 1b, Open-Label, Dose Escalation Study to Evaluate the Safety, Tolerability, Pharmacokinetics and Pharmacodynamics of MK-0482 as Monotherapy and in Combination With Pembrolizumab in Participants With Advanced/Metastatic Solid Tumors.
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Neoplasms
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2019-04-17
Enrollment: 230
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: This is a 2 part study. Part 1 is a dose escalation to determine the safety and tolerability and to establish a preliminary recommended Phase 2 dose (RP2D) dose of MK-0482 administered as monotherapy and in combination with pembrolizumab (MK-3475) in participants with advanced solid tumors for which there is no available therapy which may convey clinical benefit. Part 2 is expansion cohort to determine safety and tolerability of MK-0482 in combination with pembrolizumab with and without chemotherapy in participants with advanced tumor specific cohorts.


Eligibility criteria: Inclusion Criteria:

* Part 1 only: Has histologically-or cytologically-confirmed advanced/metastatic solid tumors and have received, been intolerant to, or been ineligible for, all treatments known to confer clinical benefit
* Has measurable disease by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) or Response Assessment in Neuro-Oncology (RANO) for Cohort B as assessed by the local site investigator/radiology
* Has provided an evaluable archival or newly obtained tumor tissue sample
* Part 1, Arm 1 only: Has ≥1 discrete malignant lesions that are amenable to biopsy
* Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1
* Male participants are eligible to participate if they agree to the following during the intervention period and for at least 95 days after the last dose of chemotherapy: refrain from donating sperm plus either be abstinent from heterosexual intercourse as their preferred and usual lifestyle and agree to remain abstinent or agree to use contraception unless confirmed to be azoospermic
* A female participant is eligible to participate if she is not pregnant or breastfeeding, and ≥1 of the following conditions applies: is not a woman of childbearing potential (WOCBP) OR is using a contraceptive method that is highly effective or is abstinent from heterosexual intercourse as their preferred and usual lifestyle during the intervention period and for at least 180 days after the last dose of chemotherapy or 120 days after the last dose of MK-0482 or pembrolizumab, whichever occurs last
* Part 2 Cohort A, C, and E only: WOCBP must also agree not to donate to others or freeze/store for her own use for the purpose of reproduction during and for at least 180 days after the last dose of chemotherapy
* Has a negative highly sensitive pregnancy test within 72 hours before the first dose of study treatment
* Human immunodeficiency virus (HIV) infected participants must have well controlled HIV on anti-retroviral therapy (ART)
* Has adequate organ function
* Part 2 Cohort A only: 1) Has histologically confirmed locally recurrent inoperable or metastatic triple negative breast cancer (TNBC) 2) Has received no prior systemic therapy for metastatic TNBC 3) Has tumor programmed death ligand 1 (PD-L1) combined positive score (CPS) ≥1
* Part 2 Cohort B only: 1) Has confirmed diagnosis of GBM (isocitrate dehydrogenase (IDH) wildtype per 2021 World Health Organization (WHO) classification of tumors of central nervous system) 2) Has received a standard first-line treatment for GBM including surgery and radiation therapy with or without chemotherapy and evidence of disease recurrence or pression by magnetic resonance imaging (MRI) 3) Has time elapsed from prior treatment as per protocol 4) Has Karnofsky performance status (KPS) ≥ 80 within 7 days before start of study treatment 5) Is neurologically stable 6) Has known status of O6-methylguanine-DNA methyltransferase (MGMT) methylation and isocitrate dehydrogenase (IDH)
* Part 2 Cohort C only: Has histologically confirmed diagnosis of metastatic PDAC and has received no prior systemic therapy for metastatic pancreatic ductal adenocarcinoma (PDAC) including chemotherapy, biological or targeted therapy and has albumin ≥3.0 g/dL
* Part 2 Cohort D only: Has histologically confirmed diagnosis of locally advanced or metastatic soft tissue sarcoma (STS) and has received and progressed after one prior line of systemic treatment for advanced STS. Prior treatment in the (neo)adjuvant setting is not counted as a line of treatment for advanced disease
* Part 2 Cohort E only: Has histologically confirmed diagnosis of Stage IV or recurrent non-operable non-squamous non-small cell lung carcinoma (NSCLC) , has confirmation that epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), or c-ros oncogene 1 (ROS1) directed therapy is not indicated as primary therapy and has not received prior systemic treatment for metastatic NSCLC

Exclusion Criteria:

* Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years
* Has a known additional malignancy that is progressing or has required active treatment within the past 2 years; with the exception of basal cell carcinoma of the skin, squamous cell carcinoma of the skin, superficial bladder cancer, or carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) that have undergone potentially curative therapy
* Has known active central nervous system metastases and/or carcinomatous meningitis
* Has had a severe hypersensitivity reaction to treatment with a monoclonal antibody (mAb) and/or any component of pembrolizumab (MK-3475) or MK-0482
* Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher immune-related adverse event (irAE)
* Has an active infection requiring systemic therapy
* Has a history of interstitial lung disease
* Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis
* Has an active autoimmune disease that has required systemic treatment in the past 2 years
* HIV-infected participants with a history of Kaposi's sarcoma and/or Multicentric Castleman's Disease
* Has known Hepatitis B or C infection
* Has received prior systemic anticancer therapy, definitive radiotherapy, including investigational agents within 4 weeks (2 weeks for palliative radiation) before the first dose of study treatment
* Has received a live or live-attenuated vaccine within 30 days before the first dose of study treatment
* Has received an investigational agent or has used an investigational device 4 weeks prior to start of study intervention
* Has a diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy or any other form of immunosuppressive therapy within 7 days prior the first dose of study treatment
* Has had an allogeneic tissue/solid organ transplant in the last 5 years or has evidence of graft-versus-host disease
* Part 2 only: Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or prior therapy targeting other immune-regulatory receptors or mechanisms
* Part 2 Cohort A only: 1) Has a history of class II-IV congestive heart failure or myocardial infarction within 6 months of start of study treatment 2) Has a known sensitivity to any component of paclitaxel or any of its excipients and 3) Is receiving any medication prohibited in combination with paclitaxel unless medication was stopped within 7 days before the start of study treatment
* Part 2 Cohort B only: 1) Has carcinomatous meningitis 2) Has recurrent tumor 3) Has tumor primarily localized to the brainstem or spinal cord 4) Has presence of multifocal tumor, diffuse leptomeningeal or extracranial disease 5) Has evidence of intratumoral or peritumoral hemorrhage on baseline MRI scan except Grade ≤ Grade I and either post-operative OR stable on at least 2 consecutive MRI scans 6) Requires treatment with moderate or high dose systemic corticosteroids as defined in protocol for at least 3 consecutive days within 2 weeks of start of study treatment and 7) Optune® TTFields within 2 weeks of start of study treatment
* Part 2 Cohort C only: 1) Has a history of class II-IV congestive heart failure, cerebral vascular event, unstable angina, or myocardial infarction within 6 months of the start of study treatment 2) Has symptomatic ascites, and 3) Has a known hypersensitivity to nab-paclitaxel or gemcitabine, or any of their excipients
* Part 2 Cohort E only: 1) Has a diagnosis of small cell lung cancer 2) Has symptomatic ascites or pleural effusion 3)Is currently receiving either strong or moderate inhibitors and/or inducers of CYP3A4 or CYP2C8 that cannot be discontinued for the duration of the study 4) Is unable to interrupt aspirin or other NSAIDs, other than aspirin dose ≤1.3 g/day for a 5-day period 5) Is unable or unwilling to take folic acid or vitamin B12 supplementation, and 6) has a known hypersensitivity to carboplatin or pemetrexed, or any of their excipients

Primary outcomes:
measure: Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Part 1 only)
timeFrame: Cycle 1 (Up to 21 days)
measure: Number of Participants Who Experience at Least One Adverse Event (AE)
timeFrame: Up to approximately 27 months
measure: Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
timeFrame: Up to approximately 24 months
measure: Number of Participants Who Experience a Dose-Limiting Toxicity (DLT) Graded Using National Cancer Institute Common Terminology Criteria for Adverse Events Version 4.0 (Part 2 only)
timeFrame: Up to approximately 28 days from the start of study intervention
Secondary outcomes:
measure: Minimum Serum Concentration (Cmin) of MK-0482 When Administered as Monotherapy (Part 1 only)
timeFrame: At designated time points (Up to approximately 25 months)
measure: Cmin of MK-0482 When Administered in Combination with Pembrolizumab (Part 1 only)
timeFrame: At designated time points (Up to approximately 25 months)
measure: Maximum Serum Concentration (Cmax) of MK-0482 When Administered as Monotherapy (Part 1 only)
timeFrame: At designated time points (Up to approximately 25 months)
measure: Cmax of MK-0482 When Administered in Combination with Pembrolizumab (Part 1 only)
timeFrame: At designated time points (Up to approximately 25 months)
measure: Area Under the Concentration-Time Curve (AUC) of MK-0482 When Administered as Monotherapy (Part 1 only)
timeFrame: At designated time points (Up to approximately 25 months)
measure: AUC of MK-0482 When Administered in Combination with Pembrolizumab (Part 1 only)
timeFrame: At designated time points (Up to approximately 25 months)
measure: Objective Response Rate (ORR) As Assessed by Investigator per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) (Part 2 only)
timeFrame: Up to approximately 25 months
measure: ORR As Assessed by Investigator per Response Assessment in Neuro-Oncology (RANO) (Part 2 only)
timeFrame: Up to approximately 25 months
Other outcomes:
Locations:
city: Detroit
country: United States
facility: Henry Ford Health System ( Site 0002)
state: Michigan
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center ( Site 0003)
state: New Jersey
city: San Antonio
country: United States
facility: Next Oncology ( Site 0001)
state: Texas
city: Macquarie University
country: Australia
facility: Macquarie University ( Site 0033)
state: New South Wales
city: Melbourne
country: Australia
facility: Alfred Health ( Site 0031)
state: Victoria
city: Vancouver
country: Canada
facility: BC Cancer - Vancouver Center ( Site 0010)
state: British Columbia
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 0011)
state: Ontario
city: Santiago
country: Chile
facility: FALP-UIDO ( Site 0100)
state: Region M. De Santiago
city: Santiago
country: Chile
facility: Bradfordhill-Clinical Area ( Site 0101)
state: Region M. De Santiago
city: Jerusalem
country: Israel
facility: Hadassa Ein Karem Medical Center ( Site 0022)
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center ( Site 0020)
city: Siena
country: Italy
facility: ospedale le scotte-U.O.C. Immunoterapia Oncologica ( Site 0091)
state: Toscana
city: Milano
country: Italy
facility: Istituto Europeo di Oncologia IRCCS-Divisione di Sviluppo di Nuovi Farmaci per Terapie Innovative (
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital ( Site 0061)
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center ( Site 0060)
city: Barcelona
country: Spain
facility: Hospital Clinic i Provincial ( Site 0041)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References: