1. To evaluate the progression-free-survival (PFS) in patients with ipilimumab refractory advanced MEL receiving either MK-3475 or chemotherapy.2. To evaluate the overall survival (OS) in patients with ipilimumab refractory advanced MEL receiving…
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Brief title
Condition
- Skin neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The following evaluations will be performed throughout the course of the study:
* Tumor response assessments by physical examination, and tumor imaging by CT
or magnetic resonance imaging (MRI), with strong preference for CT
* Quantitative photography of cutaneous lesions if indicated
* Anti-MK-3475 antibodies (MK-3475 patients only)
* PK measurements (for assessment of Ctrough and terminal half-life)
* ECOG performance status
* Tumor biopsies
The following HRQoL questionnaires will be performed up to Week 36 as well as
the End of Treatment, and 30-day Safety Follow-up visit.
* EORTC QLQ-C30
* EuroQol EQ-5D
* Health Economic Assessment
Secondary outcome
N/A
Background summary
The programmed cell death 1 (PD-1) pathway represents a major immune control
switch which may be engaged by tumor cells to overcome active T-cell immune
surveillance. The ligands for PD-1 (PD-L1 and PD-L2) are constitutively
expressed or can be induced in various tumors. High expression of PD-L1 on
tumor cells (and to a lesser extent of PD-L2) has been found to correlate with
poor prognosis and survival in various cancer types, including renal cell
carcinoma (RCC), MEL, pancreatic carcinoma, hepatocellular carcinoma, and
ovarian carcinoma. Furthermore, PD-1 has been suggested to regulate
tumor-specific T-cell expansion in patients with malignant MEL.
Preclinical in vitro and in vivo experiments have shown that PD-1 and/or PD-L1
blockade using monoclonal antibodies (mAb) enhances tumor-cell specific T-cell
activation, cytokine production, anti-tumor effector mechanisms, and clearance
of tumor cells by the immune system. Recent data of MDX-1106, an IgG4 antibody
against PD-1, have validated PD-1 as an attractive target for clinical
therapeutic intervention. MDX-1106 was tested in multiple solid tumors and
promising clinical activity was noted in MEL, RCC, and non small cell lung
carcinoma (NSCLC). The most common adverse events (AEs) were immune-related
(also referred to as AEs of special interest), with an overall incidence of
approximately 20%. Most commonly observed were pruritus, skin rash, and
diarrhea. Other immune-related AEs (irAEs) include increase of TSH, increase of
ALT/AST, pneumonitis, infusion reaction and vitiligo.
MK-3475 (previously known as SCH 900475) is a potent and highly selective
humanized mAb of the IgG4/kappa isotype designed to directly block the
interaction between PD-1 and its ligands, PD-L1 and PD-L2. The pharmacological
attributes of MK-3475 appear to be similar to those of a MDX-1106 analogue mAb
(5C4) based on preclinical studies, pharmacokinetics (PK), affinity for the
PD-1 receptor, inhibition of PD-L1 binding to the PD-1 receptor, and activity
in a functional ex vivo T-cell modulation assay (for details see the MK-3475
Investigator*s Brochure).
An open label Phase I study (Protocol 001) is being conducted to evaluate the
safety and clinical activity of single agent MK-3475. The dose escalation
portion of this study evaluated three dose levels, 1 mg/kg, 3 mg/kg, and 10
mg/kg, administered every 2 weeks, in patients with advanced solid tumors. All
three dose levels were well tolerated and no dose-limiting toxicities were
observed. Based on PK data showing a half-life of 21 days, the protocol was
amended to change the dosing frequency in the expansion cohort to every 3 weeks
(Q3W). Preliminary evidence of antitumor activity was observed in MEL and
NSCLC. Two patients with metastatic MEL showed confirmed objective responses
based on the Response Evaluation Criteria in Solid Tumors (RECIST 1.1). The
ongoing expansion cohort in Protocol 001 is enrolling metastatic MEL patients
and promising preliminary anti-cancer activity was observed (4/10 objective
responses; all centrally reviewed RECIST 1.1) in MEL patients. Forty-six (46)
patients who were previously treated with ipilimumab were treated with
MK-3475. Anti-cancer activity in this population was observed (unpublished
internal data). Anti-cancer activity by PD-1mAb seen in MEL patients thus far
provide a strong rationale for testing MK-3475 in patients who progressed after
ipilimumab.
Despite recent approval of ipilimumab (for patients with MEL) and vemurafenib
(for patients with BRAF V600E mu MEL), the overall outlook for patients with
metastatic MEL is bleak. A great majority of patients treated with ipilimumab
will not receive significant clinical benefit with ~70% of the patients in the
registration trial having a best overall response of PD. While ~50% of patients
experience objective responses with vemurafenib, most of these patients will
experience disease progression shortly after a response is achieved (median
Progression Free Survival of <7 months). Treatment options for these patients
are limited to cytotoxic chemotherapies, which have not shown survival benefits
in the past. MK-3475 has the opportunity to improve clinical outcome of this
population of unmet medical need.
The current study will examine the efficacy of 2 mg/kg of MK-3475 and 10 mg/kg
of MK-3475 Q3W versus chemotherapy (treatment of Investigator choice) in
patients with advanced MEL who are refractory to ipilimumab. Patients with BRAF
V600E mu MEL have also been previously treated with a BRAF and/or MEK
inhibitor. Chemotherapy choices to be delivered according to standard of care
(SOC) or current clinical practice for the treatment of MEL are carboplatin
plus paclitaxel, paclitaxel alone, dacarbazine (DTIC), and temozolomide.
Study objective
1. To evaluate the progression-free-survival (PFS) in patients with ipilimumab
refractory advanced MEL receiving either MK-3475 or chemotherapy.
2. To evaluate the overall survival (OS) in patients with ipilimumab refractory
advanced MEL receiving either MK-3475 or chemotherapy.
Study design
Patients will be randomized in a 1:1:1 ratio to receive blinded MK-3475 2 mg/kg
or MK-3475 10 mg/kg, or chemotherapy (treatment of Investigator choice). Only
the MK-3475 doses will be blinded to the Investigator and patient. Screening
results of qualified patients will be entered into the Interactive Voice
Response System (IVRS)/IXRS (a system that offers phone and web access
functionality) and patients will be assigned to receive MK-3475 (double-blinded
to 2 mg/kg or 10 mg/kg) or chemotherapy treatment of Investigator choice.
Patients assigned to the MK-3475 group will be blinded to dose level of study
drug.
Patients assigned to Investigator choice chemotherapy who experience
progression of disease (PD) per RECIST version 1.1 on chemotherapy (must be
confirmed by central review) and meet all crossover criteria at Week 12 of
study treatment, will have the opportunity to crossover to MK-3475 and receive
2 mg/kg or 10 mg/kg in a double-blind fashion. Crossover criteria for
chemotherapy patients are: 1) Eastern Cooperative Oncology Group (ECOG)
Performance Status 0-1; 2) no new known brain metastases or signs or symptoms
indicating brain metastases; 3) chemotherapy induced adverse events must have
improved to CTCAE (Version 4.0) Grade *1; and 4) PD on chemotherapy that is
confirmed by central review.
The co-primary objectives of this study are to compare the overall response
rate (ORR) by Week 12, progression-free-survival (PFS) and overall survival
(OS) of MK-3475 versus chemotherapy. In addition, assessment of PK, safety,
response duration, OS at Week 12, disease control rate (DCR) by Week 12 and
health-related quality of life (HRQoL) measures will be performed.
Two interim analyses (IA) will be performed; the first, after 120 patients have
completed 3 months of follow up (approximately 10 months from study start) and
the second, after 240 patients have completed 3 months of follow up
(approximately 13 months from study start). The objective of the first IA is
to allow discontinuing one MK-3475 arm if it is clearly not as effective as the
other MK-3475 arm. The primary objective of the second IA is to demonstrate
superiority of MK-3475 over the control arm in ORR and PFS.
Intervention
Completion of questionnaires, physical examination, ECG, blood draw, CT or MRI
scan, intravenous administration of MK3475 every 3 weeks.
Study burden and risks
Based on results from the nonclinical studies, there are currently no specific
safety considerations.
MK-3475 is a humanized monoclonal Ab. Thus far, serious infusion reactions have
been infrequent and manageable. However, subjects should be closely monitored
for potential adverse reactions during antibody infusion and potential adverse
events throughout the study. In the event that a subject experiences an
allergic reaction to MK-3475, treatment (i.e., vasopressors, H2-blockers,
antihistamines, H1-blockers, steroids) should be administered, as appropriate,
and prophylaxis should be considered. Surveillance for the appearance of HAH is
included in all protocols.
MK-3475 has the same mechanism of action as BMS 936558. Preclinical studies
have suggested similar potency, and PK modeling has suggested similar human PK.
Accordingly, the adverse events observed with BMS 936558 may serve as in
indicator for the adverse events to expect for MK-3475 in cancer patients.
Immune-related AEs (irAEs) are of special interest because of the mechanism of
action of anti-PD-1 and prior experience with anti*CTLA-4 mAbs. Up to the
cut-off date for this IB, the only possibly irAEs included pneumonitis (Grade
2), arthralgia and myalgia. One case of intestinal perforation was not
considered immune related.
Overall, MK-3475 has been safe and well tolerated.
Risks: blood draw, ECG, CT/MRI scan, intravenous injection, biopsy procedure,
and possible adverse effects of MK3475
For future biomedical research, risks to the subject have been minimized.
Risks include those associated with venipuncture to obtain the whole blood
specimen. This specimen will be obtained at the time of routine blood
specimens drawn in the main study.
Merck has developed strict security, policies and procedures to address subject
data privacy concerns. Data privacy risks are largely limited to rare
situations involving possible breach of confidentiality. In this highly
unlikely situation there is risk that the information, like all medical
information, may be misused.
It is necessary for subject-related data (i.e., ethnicity, diagnosis, drug
therapy and dosage, age, toxicities, etc) to be reassociated to double coded
specimens at the time of data analysis. These subject data will be kept in a
separate, secure Merck database, and all specimens will be stripped of subject
identifiers. No information concerning results obtained from future biomedical
research will be entered into clinical records, nor will it be released to
outside persons or agencies, in any way that could be tied to an individual
subject.
Waarderweg 39
Haarlem 2031 BN
NL
Waarderweg 39
Haarlem 2031 BN
NL
Listed location countries
Age
Inclusion criteria
1) Patient must have a histologically or cytologically confirmed diagnosis of unresectable stage III or metastatic MEL not amenable to local therapy.
2) Patients must be refractory to IPI.
3) Resolution/improvement of IPI-related AEs (including irAEs) back to Grade 0-1 and *10 mg/day prednisone (or equivalent dose) for irAEs for at least 2 weeks prior to the first dose of study drug.
4) Patients must consent to provide a newly obtained tumor tissue/biopsy (or specimen obtained within 60 days prior to consenting) for biomarker analysis from a core or excisional biopsy of a tumor lesion not previously irradiated.
5) BRAF V600E or V600K mutation status must be known at Screening. Patients with BRAF mutant melanoma must have had a prior treatment regimen that included vemurafenib, dabrafenib, or an approved BRAF and/or MEK inhibitor.
6) Patient must have at least 1 radiologically measurable lesion as per RECIST 1.1 (Appendix 6.1) defined as a lesion that is 10 mm in longest diameter or lymph node that is 15 mm in short axis imaged by CT scan or MRI.
7) Patient is *18 years of age on day of signing informed consent.
8) Patient must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) Performance Scale (Appendix 6.4).
9) Patient must have adequate organ function.
10) Patient has voluntarily agreed to participate by giving written informed consent/assent for the trial. The patient may also provide consent/assent for future biomedical Research. However, the subject may participate in the main trial without participating in Future Biomedical Research.
11) Female patient of childbearing potential should have a negative urine or serum pregnancy test within 72 hours prior to receiving the first dose of study medication. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The serum pregnancy test must be negative for the patient to be eligible.
12) Female patients enrolled in the study, who are not free from menses for > 2 years, post hysterectomy/oophorectomy, or surgically sterilized, must be willing to use either 2 adequate barrier methods or a barrier method plus a hormonal method of contraception to prevent pregnancy, or to abstain from heterosexual activity throughout the study, starting with Visit 1 through 120 days after the last dose of study drug. Approved contraceptive methods include 2 of the following methods (or 1 of the following methods combined with hormonal contraceptive), for example: intra-uterine device, diaphragm with spermicide, cervical cap with spermicide, male condoms, or female condom with spermicide. Spermicides alone are not an acceptable method of contraception.
13) Male patients must agree to use an adequate method of contraception starting with Visit 1 through 120 days after the last dose of study drug.
Exclusion criteria
1)Patient who has had chemotherapy, radioactive, or biological cancer therapy within 4 weeks prior to the first dose of study drug, or who has not recovered to CTCAE Grade 1 or better from the AEs due to cancer therapeutics administered more than 4 weeks earlier.
2) Patient who received IPI only as an adjuvant therapy.
3) Patient is currently participating or has participated in a study of an investigational agent or using an investigational device within 30 days of the first dose of study drug.
4) Patient is expected to require any other form of systemic or localized antineoplastic therapy while on study.
5) Patient is on chronic systemic steroid therapy (>10 mg/day prednisone or equivalent) within 2 weeks before the planned date for first dose randomized treatment or on any other form of immunosuppressive medication. (Patients that are expected to require premedication with corticosteroid for pembrolizumab will not be eligible for this study.)
6) Patient has a known history of a hematologic malignancy, primary central nervous system (CNS) malignancy or sarcoma, or of another primary solid tumor, unless the patient has undergone potentially curative therapy with no evidence of that disease for 5 years.
7) Patient has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
8) Patient previously had a severe hypersensitivity reaction to treatment with another mAb.
9) Patient has an active autoimmune disease or a history of autoimmune disease or syndrome that requires systemic steroids or immunosuppressive agents. Patients with vitiligo or resolved childhood asthma/atopy would be exceptions to this rule. Patients that require intermittent use of bronchodilators or local steroid injections would not be excluded from the study. Patients with hypothyroidism stable on hormone replacement will not be excluded from the study.
10) Patients who received treatment with live vaccines within 30 days prior to the first dose of study medication. Examples of live vaccines include, but are not limited to, the following: measles, mumps, rubella, chicken pox, yellow fever, seasonal flu, H1N1 flu, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine.
11) Patient had prior treatment with any other anti-PD-1, or PD-L1 or PD-L2 agent.
12) Patient has previously participated in Merck pembrolizumab clinical trials.
13) Patient has an active infection requiring systemic therapy.
14) Patient has known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies)
15) Patient is positive for active Hepatitis B (HBsAg reactive) or Hepatitis C (HCV ribonucleic acid [RNA] [qualitative] is detected). Patients with negative Hepatitis C antibody testing may not require RNA testing if deemed appropriate by treating physician.
16) Patient has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the patient's participation for the full duration of the study, or is not in the best interest of the patient to participate, in the opinion of the treating investigator.
17) Patient has known psychiatric or substance abuse disorders that would interfere with cooperation requirements of the trial.
18) Patient is, at the time of signing informed consent, a regular user (including "recreational use") of any illicit drugs or had a recent history (within the last year) of substance abuse (including alcohol).
19) Patient is pregnant or breastfeeding, or expecting to conceive or father children within the projected duration of the study, starting with the Pre-screening or Screening visit through 120 days after the last dose of study medication.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-003030-17-NL |
| CCMO | NL41716.056.12 |
| Other | Nog niet bekend |