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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/ct2/show/NCT03918278




Registration number
NCT03918278
Ethics application status
Date submitted
15/04/2019
Date registered
17/04/2019
Date last updated
12/03/2024

Titles & IDs
Public title
A Study of MK-0482 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-0482-001)
Scientific 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.
Secondary ID [1] 0 0
MK-0482-001
Secondary ID [2] 0 0
0482-001
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Neoplasms 0 0
Condition category
Condition code

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Other interventions - MK-0482
Other interventions - pembrolizumab
Treatment: Drugs - Paclitaxel
Treatment: Drugs - Nab-paclitaxel
Treatment: Drugs - Gemcitabine
Treatment: Drugs - Carboplatin
Treatment: Drugs - Pemetrexed

Experimental: Part 1: MK-0482 Monotherapy - Participants receive escalating doses of MK-0482 via intravenous (IV) infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 administrations (up to approximately 2 years).

Experimental: Part 1: MK-0482 + Pembrolizumab Combination Therapy - Participants receive escalating doses of MK-0482 via IV infusion + pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) for up to 35 administrations (up to approximately 2 years).

Experimental: Part 2: Cohort A - Participants with metastatic triple negative breast cancer (TNBC) first line treatment (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years) and paclitaxel 90 mg/m^2 via IV infusion until PD or discontinuation.

Experimental: Part 2: Cohort B - Participants with recurrent non-operable glioblastoma (GBM) current treatment of second line (2L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years).

Experimental: Part 2: Cohort C - Participants with metastatic pancreatic ductal adenocarcinoma (PDAC) (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years), Nab-Paclitaxel 125 mg/m^2 via IV infusion and gemcitabine 1000 mg/m^2 via IV infusion until PD or unacceptable toxicity that requires discontinuation.

Experimental: Part 2: Cohort D - Participants with metastatic soft tissue sarcoma (STS) (2L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years).

Experimental: Part 2: Cohort E - Participants with metastatic non-squamous non-small cell lung carcinoma (NSCLC) (1L) receive MK-0482 via IV infusion plus pembrolizumab 200 mg via IV infusion plus Pemetrexed 500 mg/m^2 via IV infusion on Day 1 of each 21-day cycle (Q3W) up to 35 administrations (up to approximately 2 years) plus carboplatin with desired dose of area under the curve (AUC) 5 and pemetrexed 500 mg/m^2, both administered via IV infusion, followed by maintenance therapy with pemetrexed 500 mg/m^2 via IV infusion for up to a total of 35 administrations (up to approximately 2 years).


Other interventions: MK-0482
IV infusion

Other interventions: pembrolizumab
IV infusion

Treatment: Drugs: Paclitaxel
IV infusion

Treatment: Drugs: Nab-paclitaxel
IV infusion

Treatment: Drugs: Gemcitabine
IV infusion

Treatment: Drugs: Carboplatin
IV infusion

Treatment: Drugs: Pemetrexed
IV infusion
Intervention code [1] 0 0
Other interventions
Intervention code [2] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
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)
Timepoint [1] 0 0
Cycle 1 (Up to 21 days)
Primary outcome [2] 0 0
Number of Participants Who Experience at Least One Adverse Event (AE)
Timepoint [2] 0 0
Up to approximately 27 months
Primary outcome [3] 0 0
Number of Participants Who Discontinue Study Treatment Due to an Adverse Event (AE)
Timepoint [3] 0 0
Up to approximately 24 months
Primary outcome [4] 0 0
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)
Timepoint [4] 0 0
Up to approximately 28 days from the start of study intervention
Secondary outcome [1] 0 0
Minimum Serum Concentration (Cmin) of MK-0482 When Administered as Monotherapy (Part 1 only)
Timepoint [1] 0 0
At designated time points (Up to approximately 25 months)
Secondary outcome [2] 0 0
Cmin of MK-0482 When Administered in Combination with Pembrolizumab (Part 1 only)
Timepoint [2] 0 0
At designated time points (Up to approximately 25 months)
Secondary outcome [3] 0 0
Maximum Serum Concentration (Cmax) of MK-0482 When Administered as Monotherapy (Part 1 only)
Timepoint [3] 0 0
At designated time points (Up to approximately 25 months)
Secondary outcome [4] 0 0
Cmax of MK-0482 When Administered in Combination with Pembrolizumab (Part 1 only)
Timepoint [4] 0 0
At designated time points (Up to approximately 25 months)
Secondary outcome [5] 0 0
Area Under the Concentration-Time Curve (AUC) of MK-0482 When Administered as Monotherapy (Part 1 only)
Timepoint [5] 0 0
At designated time points (Up to approximately 25 months)
Secondary outcome [6] 0 0
AUC of MK-0482 When Administered in Combination with Pembrolizumab (Part 1 only)
Timepoint [6] 0 0
At designated time points (Up to approximately 25 months)
Secondary outcome [7] 0 0
Objective Response Rate (ORR) As Assessed by Investigator per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) (Part 2 only)
Timepoint [7] 0 0
Up to approximately 25 months
Secondary outcome [8] 0 0
ORR As Assessed by Investigator per Response Assessment in Neuro-Oncology (RANO) (Part 2 only)
Timepoint [8] 0 0
Up to approximately 25 months

Eligibility
Key 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
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key 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

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Phase
Phase 1
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Active, not recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
Actual
19/06/2019
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
19/02/2025
Actual
Sample size
Target
230
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,VIC
Recruitment hospital [1] 0 0
Macquarie University ( Site 0033) - Macquarie University
Recruitment hospital [2] 0 0
Alfred Health ( Site 0031) - Melbourne
Recruitment postcode(s) [1] 0 0
2109 - Macquarie University
Recruitment postcode(s) [2] 0 0
3004 - Melbourne
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Michigan
Country [2] 0 0
United States of America
State/province [2] 0 0
New Jersey
Country [3] 0 0
United States of America
State/province [3] 0 0
Texas
Country [4] 0 0
Canada
State/province [4] 0 0
British Columbia
Country [5] 0 0
Canada
State/province [5] 0 0
Ontario
Country [6] 0 0
Chile
State/province [6] 0 0
Region M. De Santiago
Country [7] 0 0
Israel
State/province [7] 0 0
Jerusalem
Country [8] 0 0
Israel
State/province [8] 0 0
Ramat Gan
Country [9] 0 0
Italy
State/province [9] 0 0
Toscana
Country [10] 0 0
Italy
State/province [10] 0 0
Milano
Country [11] 0 0
Korea, Republic of
State/province [11] 0 0
Seoul
Country [12] 0 0
Spain
State/province [12] 0 0
Barcelona

Funding & Sponsors
Primary sponsor type
Commercial sector/Industry
Name
Merck Sharp & Dohme LLC
Address
Country

Ethics approval
Ethics application status

Summary
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.
Trial website
https://clinicaltrials.gov/ct2/show/NCT03918278
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Medical Director
Address 0 0
Merck Sharp & Dohme LLC
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Address 0 0
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for scientific queries



Summary Results

For IPD and results data, please see https://clinicaltrials.gov/ct2/show/NCT03918278