Clinical trial NCT03564691: Study of MK-4830 as Monotherapy and in Combination With Pembrolizumab (MK-3475) in Participants With Advanced Solid Tumors (MK-4830-001)
Official title: A Phase 1 Open Label, Multi-Arm, Multicenter Study of MK-4830 as Monotherapy and in Combination With Pembrolizumab for Participants With Advanced Solid Tumors
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Neoplasms
Keywords: PD1
PD-1
PDL1
PD-L1
Lead sponsor: Merck Sharp & Dohme LLC
Sponsor class: INDUSTRY
First posted: 2018-06-21
Enrollment: 442
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Arms are parallel, except that participants who progress by either clinical or radiographic evaluation on monotherapy with MK-4830 (Dose Escalation, Part B), may switch over into the combination therapy arm of MK-4830 and pembrolizumab (Dose Escalation, Part C), provided they meet eligibility criteria. All arms are non-randomized except Dose Expansion Arms E and F, with randomization of eligible participants between those two arms.
Primary purpose: TREATMENT

Brief summary: This study consists of several parts: dose escalation, dose expansion, dose expansion in Chinese participants residing in China, and coformulation. Dose escalation is to evaluate the safety, tolerability, and preliminary efficacy of MK-4830 monotherapy administration (Arms A and B) and in combination with pembrolizumab (Arm C). Dose expansion is to evaluate the objective response rate (ORR) of MK-4830 in combination with pembrolizumab (Arms A-F); evaluate the safety and tolerability of MK-4830 administered in combination with pembrolizumab, carboplatin, and pemetrexed (Arm G) and of MK-4830 administered in combination with pembrolizumab and lenvatinib (Arm H); evaluate the safety, tolerability and ORR of MK-4830 in combination with pembrolizumab plus chemotherapy (Arms I-L); and evaluate the safety and tolerability of MK-4830 in combination with pembrolizumab in Chinese participants from China (Arm M). The coformulation part (Arm N) evaluates the safety and tolerability of MK-4830A (coformulation of MK-4830 800 mg + pembrolizumab 200 mg). There is no formal hypothesis testing in this study.


Eligibility criteria: Inclusion Criteria:

* Dose escalation participants: Has any histologically- or cytologically-confirmed advanced/metastatic solid tumor by pathology report and has received, has been intolerant to, or has been ineligible for all treatment known to confer clinical benefit. Solid tumors of any type are eligible for enrollment
* Has measurable disease by Response Evaluation Criteria In Solid Tumors version 1.1 (RECIST 1.1), Response Assessment in Neuro-Oncology (RANO), or modified RECIST (mRECIST) as assessed by the local site investigator/radiology
* Submits an evaluable baseline tumor sample for analysis (either a recent or archival tumor sample). This inclusion criterion does not apply to Expansion phase Arm M
* Dose Escalation Part C and Back-fill participants: Has 1 or more discrete malignant lesions that are amenable to biopsy
* Has a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale. This inclusion criterion does not apply to Expansion phase Arm B
* Demonstrates adequate organ function
* A male participant must agree to use an approved contraception(s) during the treatment period and for at least 180 days after the last dose of study treatment and refrain from donating sperm during this period
* A female participant is eligible to participate if she is not pregnant, not breastfeeding, and either not a woman of childbearing potential (WOCBP) OR if a WOCBP agrees to follow the study contraceptive guidance during the treatment period and for at least 180 days after the last dose of study treatment
* Expansion phase Arm A participants:

  * Has histologically or cytologically confirmed metastatic pancreatic adenocarcinoma
  * Received at least 1 prior line of therapy and no more than 3 prior lines of systemic therapy
* Expansion phase Arm B participants:

  * Has histologically or cytologically confirmed unresectable glioblastoma multiforme (GBM) or its variants
  * Has a Karnofsky performance status (KPS) ≥ 70
  * Has had no more than 1 prior line of therapy for GBM. Radiation with or without chemotherapy is acceptable as the prior treatment
  * Has shown unequivocal evidence for tumor progression by magnetic resonance imaging (MRI) or computed tomography (CT) scan by contrast within 2 weeks prior to randomization
  * Has an interval of at least 3 weeks (to randomization) between prior surgical resection (one week for stereotactic biopsy)
  * Has an interval of at least 12 weeks from the completion of radiation therapy to randomization unless there is unequivocal histologic confirmation of tumor progression or radiographic progression outside of the prior radiation field
  * Is neurologically stable (eg, without a progression of neurologic symptoms or requiring escalating doses of systemic steroid therapy within last 2 weeks) and clinically stable
* Expansion phase Arm C participants:

  * Has histologically confirmed recurrent or metastatic head and neck squamous cell cancer (HNSCC) of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies
  * Has experienced disease progression at any time during or after treatment with a platinum-containing (eg, carboplatin or cisplatin) regimen with or without cetuximab
* Expansion phase Arm D participants:

  * Has histologically confirmed advanced or metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, and/or larynx that is considered incurable by local therapies
  * Has not had any prior programmed cell death 1 (PD-1)/ programmed cell death ligand 1 (PD-L1) therapy
* Expansion phase Arms E and F participants:

  * Has a histologically or cytologically confirmed diagnosis of advanced (Stage IIIb) or Stage IV metastatic non-small-cell lung cancer (NSCLC)
  * Has received no prior systemic therapy for chemotherapy or other targeted or biological antineoplastic therapy treatment for Stage IIIb or Stage IV metastatic NSCLC. Treatment with chemotherapy and/or radiation as part of neoadjuvant/adjuvant therapy is allowed if therapy was completed at least 6 months prior to the diagnosis of advanced disease. Participants with prior treatment with an anti-PD-1 or PD-L1 agent are not eligible
* Expansion phase Arm G participants:

  * Has a histologically or cytologically confirmed diagnosis of advanced (Stage IIIb) or Stage IV metastatic nonsquamous NSCLC (American Joint Committee on Cancer (AJCC) version 8)
  * Is able to tolerate chemotherapy with carboplatin and pemetrexed
  * Has received no prior systemic therapy for advanced NSCLC
* Expansion phase Arm H participants:

  * Has histologically confirmed diagnosis of renal cell cancer (RCC) with clear cell component with or without sarcomatoid features
  * Has locally advanced/metastatic disease or has recurrent disease
  * May have received 1 or 2 prior lines of systemic therapy for advanced RCC
* Expansion phase Arm I participants:

  * Has histologically confirmed diagnosis of recurrent and/or metastatic gastric or gastroesophageal junction adenocarcinoma that is considered incurable by local therapies
  * Has received and progressed on at least two prior chemotherapy regimens
  * If tumor was if human epidermal growth factor receptor 2 (HER2/neu) positive, participant must have previously received treatment with trastuzumab
* Expansion phase Arm J participants

  * Has histologically confirmed high-grade epithelial ovarian, fallopian tube or primary peritoneal carcinoma
  * Has received 1 or 2 prior lines of systemic therapy, including at least 1 prior platinum-based therapy
  * Has radiographic evidence of disease progression
  * Is a candidate for paclitaxel chemotherapy
* Expansion phase Arm K participants:

  * Has locally recurrent inoperable breast cancer OR have metastatic breast cancer not previously treated
  * Has confirmed triple-negative breast cancer (TNBC)
  * Has completed treatment for Stage I-III breast cancer, if indicated, and ≥6 months elapsed between the completion of treatment and first documented local or distant disease recurrence
  * Has been treated with (neo)adjuvant anthracycline
* Expansion phase Arm L participants:

  * Has histologically confirmed diagnosis of recurrent and/or advanced mesothelioma that is considered incurable by standard therapies
  * Is eligible to receive standard chemotherapy
* Expansion phase Arm M participants

  * Has any histologically or cytologically confirmed advanced/metastatic solid tumor by pathology report and have received, been intolerant of, been ineligible for, or refused all treatment known to confer clinical benefit
  * Has received up to 2 prior systemic regimens for the treatment of advanced/metastatic solid tumor
  * Is a Chinese participant residing in China
* Coformulation Arm N participants

  * Has any histologically- or cytologically-confirmed advanced/metastatic solid tumor by pathology report and have received, been intolerant to, been ineligible for, or refused all treatment known to confer clinical benefit

Exclusion Criteria:

* Has had chemotherapy, definitive radiation, or biological cancer therapy within 4 weeks (2 weeks for palliative radiation) prior to the first dose of study therapy, or has not recovered from any adverse events (AEs) that were due to cancer therapeutics administered more than 4 weeks earlier
* Has not recovered from all radiation-related toxicities to Grade 1 or less, requires corticosteroids, and had radiation pneumonitis
* Has a history of a second malignancy, unless potentially curative treatment has been completed with no evidence of malignancy for 2 years
* Has known untreated central nervous system metastases or known carcinomatous meningitis. This exclusion criterion does not apply to Expansion phase Arm B
* Has received any prior immunotherapy and was discontinued from that treatment due to a Grade 3 or higher immune-related AEs
* Has previously had a severe hypersensitivity reaction to treatment with a monoclonal antibody or has a known sensitivity to any component of pembrolizumab and/or chemotherapy agents
* Has an active infection requiring therapy
* Has a history or current interstitial lung disease
* Has a history of noninfectious pneumonitis that required steroids or current pneumonitis
* Has an active autoimmune disease that has required systemic treatment in the past 2 years except vitiligo or resolved childhood asthma/atopy
* Has clinically significant cardiac disease, including unstable angina, acute myocardial infarction within 6 months from Day 1 of study drug administration, or New York Heart Association Class III or IV congestive heart failure
* Has a known history of human immunodeficiency virus (HIV)
* Has a known active hepatitis B or C
* Is taking chronic systemic steroids in doses \>10 mg daily of prednisone or equivalent within 7 days prior to the first dose of trial treatment
* Has not fully recovered from any effects of major surgery without significant detectable infection. Surgical proceduress that required general anesthesia must be completed at least 2 weeks before first study treatment administration. Surgery requiring regional/epidural anesthesia must be completed at least 72 hours before first study treatment administration and participants should be recovered
* Has received a live or live-attenuated virus vaccine within 30 days prior to first dose of study intervention
* Is currently participating and receiving study therapy in a study of an investigational agent or has participated and received study therapy in a study of an investigational agent or has used an investigational device within 28 days of administration of MK-4830
* All Expansion phase participants:

  * Tumor types with known MSI-high status are not eligible
* Expansion phase Arm A participants:

  * Has received more than 3 lines of prior therapy for advanced disease (pancreatic cancer)
* Expansion phase Arm B participants:

  * Has tumor primarily localized to the brainstem or spinal cord
  * Has presence of diffuse leptomeningeal disease or extracranial disease
  * Has recurrent tumor greater than 6 cm in maximum diameter
  * Requires treatment with moderate or high dose systemic corticosteroids for at least 3 days within 2 weeks of randomization
* Expansion phase Arm D participants:

  * Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy treatment for their advanced metastatic HNSCC
* Expansion phase Arm E and F participants:

  * Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy treatment for their Stage IIIb or Stage IV metastatic NSCLC
  * Has had prior treatment with any anti-PD-1, PD-L1, or programmed cell death-ligand 2 (PD-L2) agent
* Expansion phase Arm G participants:

  * Has received prior systemic chemotherapy or other targeted or biological antineoplastic therapy treatment for their Stage IIIb or Stage IV nonsquamous NSCLC
  * Has had prior treatment with any anti-PD-1, PD-L1, or PD-L2 agent
* Expansion phase Arm H participants:

  * Has a clinically significant gastrointestinal (GI) abnormality
  * Has a history of untreated deep vein thrombosis or pulmonary embolism within 6 months prior to screening
  * Has poorly controlled hypertension
  * Has active GI bleeding
  * Has evidence of inadequate wound healing
  * Has active bleeding disorder or other history of significant bleeding episodes within 30 days prior to randomization
  * Has hemoptysis within 6 weeks prior to randomization
  * Has radiographic evidence of encasement or invasion of a major blood vessel, or of intratumoral cavitation
* Expansion phase Arm I participants:

  * Has experienced weight loss \> 10 % over 2 months prior to first dose of study therapy
  * Has clinical evidence of ascites
  * Has peritoneal metastases
* Expansion phase Arm J participants:

  * Has non-epithelial cancers, including borderline, malignant Müllerian mixed mucinous, malignant Brenner's tumor and undifferentiated carcinoma and/or germ cell tumors and/or sex cord - stromal tumors
  * Has received more than 2 prior lines of systemic therapy for ovarian cancer
* Expansion phase Arm K participants:

  * Has a known history of hypersensitivity or allergy to the study chemotherapies and/or any of their components
* Expansion phase Arm L participants:

  * Has a known history of hypersensitivity or allergy to the study chemotherapies and/or any of their components
  * Is receiving any medication prohibited in combination with study chemotherapies as described in the respective product labels, unless medication was stopped within 7 days prior to randomization
* All Participants (Arms A through N)

  * Has symptomatic pleural effusion (eg, cough, dyspnea, pleuritic chest pain)
  * Has had an allogenic tissue/solid organ transplant.

Primary outcomes:
measure: Dose-Limiting Toxicities (DLTs)
timeFrame: Cycle 1 (Up to 21 days)
measure: Number of Participants Who Experienced an Adverse Event (AE)
timeFrame: Up to approximately 27 months
measure: Number of Participants Who Discontinued Study Treatment Due to an AE
timeFrame: Up to approximately 24 months
measure: Objective Response Rate (ORR) per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 or Response Assessment in Neuro-Oncology (RANO) as Assessed by Investigator
timeFrame: Up to approximately 24 months
measure: ORR per Modified RECIST (mRECIST) 1.1 as Assessed by Investigator
timeFrame: Up to approximately 24 months
Secondary outcomes:
measure: Area Under the Curve (AUC) of Plasma MK-4830
timeFrame: At designated time points detailed in Description (Up to approximately 25 months)
measure: Minimum Concentration Between Doses (Ctrough) of Plasma MK-4830
timeFrame: At designated time points detailed in Description (Up to approximately 25 months)
measure: Maximum Drug Concentration (Cmax) of Plasma MK-4830
timeFrame: At designated time points detailed in Description (Up to approximately 25 months)
measure: Number of Participants Positive for Anti-Drug Antibodies (ADA) After MK-4830 plus Pembrolizumab Treatment
timeFrame: At designated time points (Up to approximately 25 months)
measure: Minimum Concentration Between Doses (Ctrough) of Plasma Pembrolizumab in Arm M
timeFrame: At designated time points detailed in Description (Up to approximately 25 months)
measure: Maximum Drug Concentration (Cmax) of Plasma Pembrolizumab in Arm M
timeFrame: At designated time points detailed in Description (Up to approximately 25 months)
Other outcomes:
Locations:
city: San Francisco
country: United States
facility: University of California at San Francisco ( Site 0004)
state: California
city: Detroit
country: United States
facility: Henry Ford Health System ( Site 0002)
state: Michigan
city: Saint Louis
country: United States
facility: Washington University ( Site 0003)
state: Missouri
city: Hackensack
country: United States
facility: John Theurer Cancer Center at Hackensack University Medical Center ( Site 0005)
state: New Jersey
city: New York
country: United States
facility: Laura and Isaac Perlmutter Cancer Center ( Site 0008)
state: New York
city: Columbus
country: United States
facility: Ohio State University Arthur G James Cancer Hospital & Richard J Solove Research Institute ( Site 00
state: Ohio
city: San Antonio
country: United States
facility: South Texas Accelerated Research Therapeutics, LLC (START) ( Site 0001)
state: Texas
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists ( Site 0011)
state: Utah
city: Seattle
country: United States
facility: Seattle Cancer Care Alliance ( Site 0010)
state: Washington
city: Liverpool
country: Australia
facility: Liverpool Hospital-Medical Oncology ( Site 0250)
state: New South Wales
city: Brisbane
country: Australia
facility: Princess Alexandra Hospital ( Site 0253)
state: Queensland
city: Hamilton
country: Canada
facility: Juravinski Cancer Centre ( Site 0034)
state: Ontario
city: Ottawa
country: Canada
facility: The Ottawa Hospital ( Site 0031)
state: Ontario
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre ( Site 0033)
state: Ontario
city: Changchun
country: China
facility: The First Hospital of Jilin University ( Site 0803)
state: Jilin
city: Shanghai
country: China
facility: Shanghai Chest Hospital-Oncology department ( Site 0801)
state: Shanghai
city: Chengdu
country: China
facility: West China Hospital of Sichuan University ( Site 0804)
state: Sichuan
city: Paris
country: France
facility: Hôpital Européen Georges Pompidou ( Site 2003)
state: Ile-de-France
city: Lille
country: France
facility: Centre Oscar Lambret ( Site 2002)
state: Nord
city: Poitiers
country: France
facility: Centre Hospitalier Universitaire de Poitiers ( Site 2000)
state: Vienne
city: Heraklion
country: Greece
facility: University General Hospital of Heraklion ( Site 0110)
state: Irakleio
city: Thessaloniki
country: Greece
facility: Euromedica General Clinic of Thessaloniki-Oncology Unit ( Site 0112)
city: Thessaloniki
country: Greece
facility: European Interbalkan Medical Center ( Site 0111)
city: Haifa
country: Israel
facility: Rambam Health Care Campus-Oncology Division ( Site 0042)
city: Petah Tikva
country: Israel
facility: Rabin Medical Center ( Site 0043)
city: Ramat Gan
country: Israel
facility: Chaim Sheba Medical Center. ( Site 0044)
city: Tel Aviv
country: Israel
facility: Sourasky Medical Center ( Site 0041)
city: Kashiwa
country: Japan
facility: National Cancer Center Hospital East ( Site 0400)
state: Chiba
city: Tokyo
country: Japan
facility: Japanese Foundation for Cancer Research ( Site 0401)
city: Seoul
country: Korea, Republic of
facility: Severance Hospital Yonsei University Health System ( Site 0300)
city: Warszawa
country: Poland
facility: Narodowy Instytut Onkologii im. Marii Sklodowskiej-Curie - Panstwowy Instytut Badawczy w Warszawie (
state: Mazowieckie
city: Gdansk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne ( Site 0151)
state: Pomorskie
city: Johannesburg
country: South Africa
facility: Wits Clinical Research ( Site 0213)
state: Gauteng
city: Durban
country: South Africa
facility: The Oncology Centre ( Site 0212)
state: Kwazulu-Natal
city: Cape Town
country: South Africa
facility: Cancercare Rondebosch Oncology ( Site 0210)
state: Western Cape
city: Hospitalet de Llobregat
country: Spain
facility: Instituto Catalan de Oncologia ICO - Hospital Duran i Reynals ( Site 0101)
state: Barcelona
city: Madrid
country: Spain
facility: Centro Integral Oncologico Clara Campal START Madrid ( Site 0102)
Study officials:
affiliation: Merck Sharp & Dohme LLC
name: Medical Director
role: STUDY_DIRECTOR
References:
citation: Siu LL, Wang D, Hilton J, Geva R, Rasco D, Perets R, Abraham AK, Wilson DC, Markensohn JF, Lunceford J, Suttner L, Siddiqi S, Altura RA, Maurice-Dror C. First-in-Class Anti-immunoglobulin-like Transcript 4 Myeloid-Specific Antibody MK-4830 Abrogates a PD-1 Resistance Mechanism in Patients with Advanced Solid Tumors. Clin Cancer Res. 2022 Jan 1;28(1):57-70. doi: 10.1158/1078-0432.CCR-21-2160. Epub 2021 Oct 1.