Surgical or Radiotherapeutic Intervention Concerning Large Singular Stable to Progressive Metastases in Patients With BRAFV600-mutated Melanoma Receiving Treatment With Encorafenib + Binimetinib
Surgical or Radiotherapeutic Intervention Concerning Large Singular Stable to Progressive Metastases in Patients With BRAFV600-mutated Melanoma Receiving Treatment With Encorafenib + Binimetinib
This is an open-label, prospective, single arm study conducted in Germany to investigate local treatment (i.e. surgery or radiotherapy or electrochemotherapy) of metastases showing no response to encorafenib (E) + binimetinib (B) combination therapy and continuation of EB therapy afterwards.
The purpose of this study is to determine PFS of individual patients treated with local intervention while continuing therapy with EB.
The purpose of this prospective study is to evaluate progression free survival (PFS) of patients being treated for a minimum of 3 months with encorafenib and binimetinib and who have non-responding metastases that will be treated with local intervention while continuing combination therapy with encorafenib and binimetinib.
Patients fulfilling the screening-criteria will receive local treatment of 1-3 metastases according to the investigator's decision and according to standard of care. Local treatments are not considered as study related treatments and will be carried out prior to registration. After registration patients will continue approved EB therapy as study treatment.
The aim of the study is to evaluate the effects of local treatment of melanoma metastases that do not respond to EB combination therapy and subsequent continuation of EB therapy on progression-free survival. Local/surgical treatment according to standard of care (= surgery, radiotherapy, electrochemotherapy) will be at the discretion of the investigator. If there are more than one metastasis to be treated locally with different methods authorization of steering committee is required.
Inclusion Criteria:
Patients may be included in the study only if they meet all the following criteria:
Signed informed consent form
Female and male patients ≥ 18 years of age
Ability to comply with the study protocol, in the investigator's judgement
Ongoing treatment with Encorafenib plus Binimetinib (EB) in accordance with the current Summary of Product Characteristics (SmPC) for a minimum of 3 months
ECOG performance status 0-2
Life expectancy ≥ 12 weeks
Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous or unknown primary melanoma (inoperable stage III or metastatic stage IV, per AJCC 8 staging)
Presence of a BRAFV600-mutation according to a validated test
Measurable disease according to RECIST v.1.1, i.e. 1 to 3 locally untreated target lesion(s) to treat with a longest diameter of ≥ 10 mm (lymph node metastases smallest diameter ≥ 15 mm) [TLT; target lesion(s) to treat which are stable or progressive under EB and subject to surgery or electrochemotherapy or radiotherapy within the study] plus ≥ 1 additional target lesion [target lesion(s), which are not subject to surgery or electrochemotherapy or radiotherapy within the study] for continuous measurement Note: Localization of TLTs will be cohortly observed.
Availability of RECIST-v1.1-compliant imaging (CT or MRT chest/ abdomen/pelvis and MRT head) within 28 days before initiation of EB treatment outside of the study (= "EB pretreatment") and within 28 days before initiation of surgery or electrochemotherapy or radiotherapy, to assess treatment response under EB pretreatment Note: Steering committee approval is required for older imaging (however, imaging older than 2 months prior to EB initiation is not allowed).
Patient must fulfill one of the following conditions (= mixed tumor response) for TLT:
Notes:
TLT must be eligible for treatment with radiotherapy or surgery (R0) or electrochemotherapy; if both, radiotherapy and surgery, required according to national guidelines (e.g., brain metastases) authorization of steering committee is required.
Patients must have recovered from all prior treatment related toxicities to NCI CTCAE v5.0 grade ≤ 1, at the time of registration (except for: toxicities not considered a safety risk such as alopecia; stable and non-EB overlapping immune-related (ir) toxicities grade ≤ 2 which are controlled, except ir colitis)
Patient with toxicities related to E and/or B [NCI CTCAE v5.0] must have recovered to grade ≤ 1 and be in a stable situation concerning such toxicities
Adequate bone marrow, organ function and lab parameters:
Adequate cardiac function:
Negative serum β-hCG test (female patient of childbearing potential only) within 72 hours prior to registration and use of a highly effective contraception for both male and female patients if the risk of conception exists throughout the study and for 4 weeks after study drug discontinuation.
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, should use a highly effective contraception method including:
Total abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation >6 weeks prior to registration; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
Male sterilization (>6 months prior to registration); for female patients on the study, the vasectomized male partner must be the sole partner for that patient
Combination of two of the following:
Note:
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
Exclusion Criteria:
Inclusion Criteria:
Patients may be included in the study only if they meet all the following criteria:
Signed informed consent form
Female and male patients ≥ 18 years of age
Ability to comply with the study protocol, in the investigator's judgement
Ongoing treatment with Encorafenib plus Binimetinib (EB) in accordance with the current Summary of Product Characteristics (SmPC) for a minimum of 3 months
ECOG performance status 0-2
Life expectancy ≥ 12 weeks
Histologically confirmed diagnosis of locally advanced, unresectable or metastatic cutaneous or unknown primary melanoma (inoperable stage III or metastatic stage IV, per AJCC 8 staging)
Presence of a BRAFV600-mutation according to a validated test
Measurable disease according to RECIST v.1.1, i.e. 1 to 3 locally untreated target lesion(s) to treat with a longest diameter of ≥ 10 mm (lymph node metastases smallest diameter ≥ 15 mm) [TLT; target lesion(s) to treat which are stable or progressive under EB and subject to surgery or electrochemotherapy or radiotherapy within the study] plus ≥ 1 additional target lesion [target lesion(s), which are not subject to surgery or electrochemotherapy or radiotherapy within the study] for continuous measurement Note: Localization of TLTs will be cohortly observed.
Availability of RECIST-v1.1-compliant imaging (CT or MRT chest/ abdomen/pelvis and MRT head) within 28 days before initiation of EB treatment outside of the study (= "EB pretreatment") and within 28 days before initiation of surgery or electrochemotherapy or radiotherapy, to assess treatment response under EB pretreatment Note: Steering committee approval is required for older imaging (however, imaging older than 2 months prior to EB initiation is not allowed).
Patient must fulfill one of the following conditions (= mixed tumor response) for TLT:
Notes:
TLT must be eligible for treatment with radiotherapy or surgery (R0) or electrochemotherapy; if both, radiotherapy and surgery, required according to national guidelines (e.g., brain metastases) authorization of steering committee is required.
Patients must have recovered from all prior treatment related toxicities to NCI CTCAE v5.0 grade ≤ 1, at the time of registration (except for: toxicities not considered a safety risk such as alopecia; stable and non-EB overlapping immune-related (ir) toxicities grade ≤ 2 which are controlled, except ir colitis)
Patient with toxicities related to E and/or B [NCI CTCAE v5.0] must have recovered to grade ≤ 1 and be in a stable situation concerning such toxicities
Adequate bone marrow, organ function and lab parameters:
Adequate cardiac function:
Negative serum β-hCG test (female patient of childbearing potential only) within 72 hours prior to registration and use of a highly effective contraception for both male and female patients if the risk of conception exists throughout the study and for 4 weeks after study drug discontinuation.
Women of child-bearing potential, defined as all women physiologically capable of becoming pregnant, should use a highly effective contraception method including:
Total abstinence when this is in line with the preferred and usual lifestyle of the patient; periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception
Female sterilization (have had surgical bilateral oophorectomy with or without hysterectomy) or tubal ligation >6 weeks prior to registration; in case of oophorectomy alone, only when the reproductive status of the woman has been confirmed by follow up hormone level assessment
Male sterilization (>6 months prior to registration); for female patients on the study, the vasectomized male partner must be the sole partner for that patient
Combination of two of the following:
Note:
A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a postmenopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient to determine the occurrence of a postmenopausal state. The above definitions are according to Clinical Trial Facilitation Group guidance. Pregnancy testing and contraception are not required for women with documented hysterectomy or tubal ligation.
Exclusion Criteria:
Patients will be excluded from the study for any of the following reasons:
Uveal or mucosal melanoma
Presence of untreated brain metastases (exception if this is TLT) Note: Treated brain metastases (stereotactic or surgical intervention) are allowed, if these are stable for > 4 weeks and off corticosteroids for > 3 weeks.
Presence of any symptomatic brain and/or leptomeningeal metastases
Any previous radiation [including stereotactic radiosurgery (SRS)] therapy involving > 25 % of bone marrow and/or ongoing ≤ 28 days prior to registration (local/surgical intervention excluded)
Any major surgery, open biopsy, or significant traumatic injury ≤ 14 days prior to screening Note: Minor surgical procedures should be completed > 7 days prior to registration.
Prior treatment with a BRAF- and/or MEK-inhibitor other than EB
Any prior systemic chemotherapy for the current melanoma disease Note: Chemotherapy given as part of isolated limb perfusion, regional or intralesional treatment will not be considered systemic treatment
Any use of an investigational agent ≤ 28 days or ≤ 5 half-lives (minimum 14 days) or an approved medication except of E + B prior to registration, whichever is shorter
Any intake of the following foods/supplements within ≤ 7 days prior to registration:
Any condition that would interfere with the planned radiotherapy or surgery or electrochemotherapy of TLT Note: If one of these therapies is without interference this should be performed in the study.
Any contraindication against the radiotherapy or surgery or electrochemotherapy of TLT Note: If one of these therapies is without contraindication this should be performed in the study.
Known hypersensitivity to any components of the study treatment
Any malabsorption condition that would alter the absorption of orally administered medications
Inability to swallow oral medication
History of allogeneic bone marrow or organ transplant requiring use of immunosuppressive medication
Known positive serology for HBV, HCV and/or HIV
Any active infection requiring systemic antibiotic therapy ≤ 2 weeks prior to registration
History or current evidence of retinal vein occlusion (RVO) or current risk factors for RVO (e.g. uncontrolled glaucoma with intraocular pressures > 21 mm HG or ocular hypertension, history of hyperviscosity or hypercoagulability syndromes)
Impaired cardiovascular function or clinically significant cardio-vascular diseases, including the following:
Neuromuscular disorders that are associated with elevated creatine phosphokinase (CK) (e.g. inflammatory myopathies, muscular dystrophy, amyotrophic lateral sclerosis, spinal muscular atrophy)
Previous or concurrent malignancy with the following exceptions:
Known alcohol or drug abuse
Any medical, psychiatric, cognitive or other conditions that would, in the investigator's judgement, prevent the patient's participation in the clinical study due to safety concerns, compliance with clinical study procedures or interpretation of study results
Participation in another trial (non-interventional studies are allowed) within 30 days prior to screening
Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive β-hCG laboratory test
Legal incapacity or limited legal capacity