Durvalumab (MEDI4736) Plus Cediranib in Patients With Metastatic Uveal Melanoma

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Brief Title

Durvalumab (MEDI4736) Plus Cediranib in Patients With Metastatic Uveal Melanoma

Official Title

Phase II, Open-Label Study of Preliminary Efficacy of Durvalumab (MEDI4736) in Combination With Cediranib in Patients With Metastatic Uveal Melanoma

Brief Summary

      Phase II clinical trial aimed to evaluate the efficacy of the combination of cediranib and
      durvalumab in patients with metastatic uveal melanoma (mUM) with biopsiable disease at first
      line of after failure to first line systemic or liver directed therapy.
    


Study Phase

Phase 2

Study Type

Interventional


Primary Outcome

Objective response rate by RECIST 1.1

Secondary Outcome

 Median Progression-free survival (PFS) by RECIST 1.1

Condition

Uveal Melanoma

Intervention

Cediranib Maleate

Study Arms / Comparison Groups

 Cediranib plus durvalumab
Description:  

Publications

* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.

Recruitment Information


Recruitment Status

Drug

Estimated Enrollment

0

Start Date

May 2020

Completion Date

December 2021

Primary Completion Date

December 2021

Eligibility Criteria

        Inclusion Criteria:

          -  Patients must have histologically confirmed metastatic uveal melanoma with measurable
             disease not eligible for curative therapy.

          -  Participants must have measurable disease, defined as at least one lesion that can be
             accurately measured in at least one dimension (longest diameter to be recorded for
             non-nodal lesions and short axis for nodal lesions) as ≥20 mm with conventional
             techniques or as ≥10 mm with spiral CT scan, MRI, or calipers by clinical exam.
             Patients must have at least 1 biopsiable liver metastasis.

          -  Patients can have received one prior therapy for metastatic disease, excepting for
             treatments listed in exclusion criteria.

          -  Patients must be 18 years of age or older at time of study entry.

          -  Eastern Cooperative Oncology Group (ECOG) Performance Status 0-1.

          -  Capable of giving signed informed consent which includes compliance with the
             requirements and restrictions listed in the informed consent form (ICF) and in the
             protocol.

          -  Adequate normal organ and marrow function as defined below: Haemoglobin ≥9.0 g/dL,
             Absolute neutrophil count (ANC) > 1.5 x 109/L (> 1500 per mm3), Platelet count ≥ 100 x
             109/L (>100,000 per mm3). Serum bilirubin ≤1.5 x institutional upper limit of normal
             (ULN). This will not apply to patients with confirmed Gilbert's syndrome (persistent
             or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of
             hemolysis or hepatic pathology), who will be allowed only in consultation with
             Coordinating Investigator. Aspartate aminotransferase (AST) and/or alanine
             aminotransferase (ALT) <2.5 x upper limit of normal (ULN) in the absence of liver
             metastases. If liver metastases are present, both AST and ALT must be no more than 5 x
             ULN. Creatinine clearance >30 ml/min calculated by Cockcroft-Gault or another
             validated method. Urine protein:creatinine ratio (UPC) ≤1 or ≤2+ proteinuria on 2
             consecutive dipsticks taken no less than 1 week apart. Subjects with 2+ proteinuria on
             dipstick must also have UPC < 0.5 on 2 consecutive samples.

          -  Postmenopausal or evidence of non-childbearing status for women of childbearing
             potential as confirmed by a negative urine or serum pregnancy test within 7 days prior
             to inclusion. Women will be considered post-menopausal if they have been amenorrheic
             for 12 months without an alternative medical cause. The following age-specific
             requirements apply: Amenorrheic for ≥1 year in the absence of chemotherapy and/or
             hormonal treatments. Luteinizing hormone (LH) and/or follicle stimulating hormone
             and/or estradiol levels in the post-menopausal range. Radiation induced oophorectomy
             with last menses >1 year ago. Chemotherapy induced menopause with >1 year interval
             since last menses. Surgical sterilization (bilateral oophorectomy or hysterectomy)
             Women <50 years of age would be considered post-menopausal if they have been
             amenorrheic for 12 months or more following cessation of exogenous hormonal treatments
             and if they have luteinizing hormone and follicle-stimulating hormone levels in the
             post-menopausal range for the institution or underwent surgical sterilization
             (bilateral oophorectomy or hysterectomy). Women ≥50 years of age would be considered
             post-menopausal if they have been amenorrheic for 12 months or more following
             cessation of all exogenous hormonal treatments, had radiation-induced menopause with
             last menses >1 year ago, had chemotherapy-induced menopause with last menses >1 year
             ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral
             salpingectomy or hysterectomy).

          -  Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

          -  Must have a life expectancy of at least 12 weeks

          -  Subjects must be able to swallow and retain oral medications and be without clinically
             significant gastrointestinal illnesses that would preclude absorption of cediranib.

          -  Adequately controlled BP: Systolic BP ≤140 mmHg and diastolic BP ≤90 mmHg in the
             presence or absence of a stable regimen of antihypertensive therapy.

        Exclusion Criteria:

          -  Patients with concomitant malignancy other than non-melanoma skin cancer, or
             superficial bladder cancer controlled with local treatment.

          -  Previous treatment with anti-angiogenic agents MEK, BRAF, ERK inhibitors.

          -  Previous treatment with anti-PD1/PDL1 (including durvalumab) treatments.

          -  Presence of brain or leptomeningeal involvement unless previously treated, off
             steroids at least 2 weeks, and considered stable. Patients with untreated central
             nervous system (CNS) metastases and/or carcinomatous meningitis identified either on
             the baseline brain imaging [RECIST]) obtained during the screening period or
             identified prior to signing the ICF. Patients whose brain metastases have been treated
             may participate provided they show radiographic stability (defined as 2 brain images,
             both of which are obtained after treatment to the brain metastases. These imaging
             scans should both be obtained at least four weeks apart and show no evidence of
             intracranial progression). In addition, any neurologic symptoms that developed either
             as a result of the brain metastases or their treatment must have resolved or be stable
             either, without the use of steroids, or are stable on a steroid dose of ≤10mg/day of
             prednisone or its equivalent and anticonvulsants, for at least 14 days prior to the
             start of treatment. Brain metastases will not be recorded as RECIST Target Lesions at
             baseline.

          -  Patients weighing <30kg will be excluded from enrollment.

          -  Participation in another clinical study with an investigational product during the
             last 4 weeks.

          -  Concurrent enrolment in another clinical study, unless it is an observational
             (non-interventional) clinical study or during the follow-up period of an
             interventional study.

          -  Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapy, endocrine
             therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
             antibodies) ≤28 days prior to the first dose of study drug If sufficient wash-out time
             has not occurred due to the schedule or PK properties of an agent, a longer wash-out
             period will be required, as agreed by Sponsor designated Coordinating Investigator and
             Principal Investigator.

          -  Any unresolved toxicity NCI CTCAE Grade ≥2 from previous anticancer therapy with the
             exception of alopecia, vitiligo, and the laboratory values defined in the inclusion
             criteria: Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis
             after consultation with the Coordinating Investigator. Patients with irreversible
             toxicity not reasonably expected to be exacerbated by treatment with durvalumab may be
             included only after consultation with the Coordinating Investigator.

          -  Any concurrent chemotherapy, IMP, biologic, or hormonal therapy for cancer treatment
             different to cediranib and/or durvalumab. Concurrent use of hormonal therapy for
             non-cancer-related conditions (e.g., hormone replacement therapy) is acceptable.

          -  Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
             radiation within 4 weeks of the first dose of study drug.

          -  Major surgery within a minimum of 2 weeks prior to inclusion; patients must have
             recovered from any effects of any major surgery prior to inclusion. Note: Local
             surgery of isolated lesions for palliative intent and minor surgeries performed to
             obtain biological material for the study (i.e. liver biopsy) are acceptable.

          -  History of allogeneic organ transplantation.

          -  Active or prior documented autoimmune or inflammatory disorders (including
             inflammatory bowel disease [e.g., colitis or Crohn's disease], diverticulitis [with
             the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome,
             or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
             arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
             criterion: Patients with vitiligo or alopecia. Patients with hypothyroidism (e.g.,
             following Hashimoto syndrome) stable on hormone replacement. Any chronic skin
             condition that does not require systemic therapy. Patients without active disease in
             the last 5 years may be included but only after consultation with the Coordinating
             Investigator. Patients with celiac disease controlled by diet alone.

          -  Uncontrolled intercurrent illness, including but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable
             angina pectoris, cardiac arrhythmia, interstitial lung disease, serious chronic
             gastrointestinal conditions associated with diarrhea, or psychiatric illness/social
             situations that would limit compliance with study requirement, compromise cediranib
             absorption, substantially increase risk of incurring AEs or compromise the ability of
             the patient to give written informed consent.

          -  History of another primary malignancy, except for: Malignancy treated with curative
             intent and with no known active disease ≥5 years before the first dose of IMP and of
             low potential risk for recurrence. Adequately treated non-melanoma skin cancer or
             lentigo maligna without evidence of disease. Adequately treated carcinoma in situ
             without evidence of disease.

          -  History of active primary immunodeficiency.

          -  Active infection including tuberculosis (clinical evaluation that includes clinical
             history, physical examination and radiographic findings, and TB testing in line with
             local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
             hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). Patients
             with a past or resolved HBV infection (defined as the presence of hepatitis B core
             antibody [anti-HBc] and absence of HBsAg) are eligible. Patients positive for
             hepatitis C (HCV) antibody are eligible only if polymerase chain reaction is negative
             for HCV RNA.

          -  Current or prior use of immunosuppressive medication within 14 days before the first
             dose of durvalumab. The following are exceptions to this criterion: Intranasal,
             inhaled, topical steroids, or local steroid injections (e.g., intra articular
             injection). Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
             prednisone or its equivalent. Steroids as premedication for hypersensitivity reactions
             (e.g., CT scan premedication).

          -  Receipt of live attenuated vaccine within 30 days prior to the first dose of IMP.
             Note: Patients, if enrolled, should not receive live vaccine whilst receiving IMP and
             up to 30 days after the last dose of IMP.

          -  Female patients who are pregnant (confirmed with positive pregnancy test) or
             breastfeeding or male or female patients of reproductive potential who are not willing
             to employ effective birth control from screening to 90 days after the last dose of
             durvalumab and or cediranib therapy.

          -  History of severe allergic reaction attributed to cediranib or a similar VEGFR
             inhibitor or known hypersensitivity to any component of cediranib dose composition.

          -  Known allergy or hypersensitivity to durvalumab or any of the durvalumab excipients.

          -  History of gastrointestinal perforation. Subjects with a history of abdominal fistula
             will be eligible if: the fistula has been surgically repaired, there is no evidence of
             fistula for at least 6 months prior to inclusion, and the subject is deemed to be at
             low risk of recurrent fistula in the opinion of the Investigator.

          -  History of intra-abdominal abscess within 3 months prior to inclusion.

          -  Clinically significant signs and/or symptoms of bowel obstruction within 3 months
             prior to inclusion.

          -  Resting ECG with clinically significant abnormal findings. i.e. Mean QT interval
             corrected for heart rate using Fridericia's formula (QTcF) ≥470 ms calculated from 3
             ECGs (within 15 minutes at 5 minutes apart).

          -  Subjects with any one or more of the following: History of myocardial infarction
             within 6 months prior to inclusion; patients with a history of myocardial infarction
             within 6 to 12 months prior to inclusion may be allowed following assessment. Unstable
             angina within 6 months prior to inclusion. Known significant cardiac disease (New York
             Heart Association [NYHA] classification of III or IV).

          -  Left ventricular ejection fraction < lower limit of normal (LLN) per institutional
             guidelines, or <55%, if threshold for normal is not otherwise specified by
             institutional guidelines, for patients with the following risk factors: Prior or
             planned treatment with anthracyclines (ie, PLD). Prior treatment with trastuzumab.
             Prior central thoracic radiation therapy (RT), including exposure of heart to
             therapeutic doses of ionizing RT. History of myocardial infarction within 6 to 12
             months prior to inclusion. Prior history of other significant impaired cardiac
             function.

          -  History of stroke or transient ischemic attack within 6 months prior to inclusion.

          -  Evidence of any other disease, physical examination or laboratory finding giving
             reasonable suspicion of a disease or condition that puts the subject at high risk for
             treatment-related complication.

          -  Prior enrollment or treatment in a previous durvalumab and/or cediranib clinical study
             regardless of treatment arm assignment.
      

Gender

All

Ages

18 Years - N/A

Accepts Healthy Volunteers

No

Contacts

José M. Piulats, , 

Location Countries

Spain

Location Countries

Spain

Administrative Informations


NCT ID

NCT04184518

Organization ID

GEM-1805

Secondary IDs

ESR-18-14002

Responsible Party

Sponsor

Study Sponsor

Grupo Español Multidisciplinar de Melanoma

Collaborators

 MFAR

Study Sponsor

José M. Piulats, Study Chair, Institut Català d'Oncología L'Hospitalet


Verification Date

May 2020