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Title A Phase 1/2, Open-label Study to Evaluate the Safety and Antitumor Activity of MEDI0680 (AMP-514) in Combination with MEDI4736 and MEDI0680 Monotherapy in Subjects with Select Advanced Malignancies

IRB MEDI1816

CC 16-1213

Hospital Main Campus

Stage Advanced/Metastatic

Phase Phase 1, Phase 2

Disease Renal

Drug Durvalumab , MEDI0680(AMP-514)

Description

Primary Objectives

• To determine the MTD or the highest protocol-defined dose in the absence of exceeding the MTD for MEDI0680 in combination with MEDI4736, and the safety profile of MEDI0680 in combination with MEDI4736 in subjects with advanced malignancies
• To evaluate the antitumor activity of MEDI0680 monotherapy and in combination with MEDI4736 in immunotherapy-na�ve subjects with advanced or metastatic ccRCC as based on investigator assessed response using RECIST v1.1 (Eisenhauer et al, 2009)

Secondary Objectives

• To evaluate the antitumor activity of MEDI0680 in combination with MEDI4736 in subjects with advanced malignancies as determined by the investigator based on modified RECIST v1.1
• To describe the safety and tolerability of MEDI0680 monotherapy and in combination with MEDI4736 in immunotherapy-na�ve subjects with advanced or metastatic ccRCC
• To evaluate the antitumor activity of MEDI0680 monotherapy and in combination with MEDI4736 in immunotherapy-na�ve subjects with advanced or metastatic ccRCC as based on blinded independent central review (BICR) assessed response using RECIST v1.1
• To describe the pharmacokinetics (PK) of MEDI0680 monotherapy and in combination with MEDI4736
• To describe the PK of MEDI4736 in combination with MEDI0680
• To determine the immunogenicity of MEDI0680 monotherapy and in combination with MEDI4736
• To determine the immunogenicity of MEDI4736 in combination with MEDI0680
• To determine whether PD-L1 is a predictive biomarker for response to therapy

Exploratory Objectives

• To identify biomarkers that are predictive of antitumor response to MEDI0680 monotherapy or in combination with MEDI4736
• To profile gene expression changes that may correlate with antitumor response to MEDI0680 monotherapy or in combination with MEDI4736
• To evaluate additional biomarkers that may correlate with antitumor activity of MEDI0680 monotherapy or in combination with MEDI4736
• To evaluate the pharmacodynamic activity of MEDI0680 monotherapy and in combination with MEDI4736 in the periphery.
• To compare the pharmacodynamic changes resulting from complete PD-1/PD-L1 pathway blockade versus treatment with MEDI0680 monotherapy
• To evaluate the antitumor activity of MEDI0680 monotherapy or in combination with MEDI4736 in subjects with advanced or metastatic ccRCC as assessed by immune-related Response Evaluation Criteria in Solid Tumors (irRECIST)

Inclusion Criteria

1. Age ≥ 18 years at the time of screening
2. ECOG performance status of 0 - 1
3. For dose escalation:
   • Histologically confirmed metastatic or recurrent NSCLC, SCCHN, MSI-high CRC, bladder cancer, ovarian cancer, esophageal cancer, gastric cancer, or RCC that are refractory or intolerant to standard therapy or for which no standard therapy exists
   • No more than 3 prior lines of systemic therapy in the recurrent or metastatic setting, including standard and investigational agents (additional criteria apply for NSCLC, see item 3e)
   • Subjects with at least one measurable lesion according to RECIST v1.1
   • Immunotherapy na�ve: Subjects must have no prior exposure to immunotherapy including but not limited to other anti-CTLA-4, anti-PD-1, or anti-PD-L1 antibodies
   • For NSCLC subjects:
     • NSCLC subjects with metastatic or recurrent disease must have received no more than 3 prior lines of therapy, or either failed to respond, relapsed, or were unable to tolerate standard treatment
     • Subjects with EGFR-activating mutations must have received an EGFR tyrosine kinase inhibitor (TKI) and subjects with anaplastic lymphoma receptor tyrosine kinase (ALK) rearrangement positive tumors must have received an ALK TKI
     • Subjects with wild-type EGFR and ALK mutation must have failed a platinumbased regimen. NOTE: Maintenance therapy following platinum doublet-based chemotherapy is not considered a separate line of therapy. Prior platinum containing adjuvant, neoadjuvant, or definitive chemoradiation therapy given for locally advanced disease is considered first line therapy only if recurrent (local or metastatic) disease developed within 6 months of completing therapy. Subjects with recurrent disease > 6 months must also have progressed after a subsequent platinum-based chemotherapy regimen given to treat the recurrence
4. For dose-expansion:
   • Histological confirmation of advanced or metastatic RCC with a clear-cell component
   • Must have received only 1 total prior systemic treatment regimen in the advanced or metastatic setting and the prior treatment must be an approved anti-angiogenic therapy regimen (including, but not limited to, sunitinib, sorafenib, pazopanib, axitinib, tivozanib, and bevacizumab), and must have evidence of radiographic progression
     • No prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti-CTLA-4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways
     • No prior treatment with an mammalian target of rapamycin (mTOR) inhibitor (including, but not limited to everolimus, temsirolimus, sirolimus, and ridaforolimus)
     • Prior cytokine therapy (eg, IL-2, IFN-α) or treatment with cytotoxics is allowed.
   • Subjects must have at least 1 measurable lesion according to RECIST v1.1. A previously irradiated lesion cannot be considered a target lesion. Radiographic disease assessment can be performed up to 28 days prior to the first dose
5. Biopsy requirements:
   • For dose escalation, subjects must consent to provide archival tumor tissue (initial and subsequent tumor biopsy samples, if possible) for correlative biomarker studies if available
   • Able and willing to give valid written consent for fresh tumor samples if required. Fresh tumor biopsies should be preferentially obtained from tumor tissues that are safely accessible as determined by the investigator and achieved via non-significant risk procedures (refer to Section 4.3.2.1). Sites are encouraged to confirm adequacy of tumor biopsy material at the time of the procedure. Fine-needle aspirate specimens are not acceptable.
   • For dose-expansion:
     • Tumor tissue (formalin fixed paraffin embedded [FFPE] archival or fresh tumor tissue) must be received by the central vendor (block or unstained slides) and evaluable for PD-L1 expression status in order to randomize a subject to study treatment.
     • All subjects are encouraged to consent to and provide both pre-treatment and on treatment fresh tumor biopsies
     • Once the initial 50 subjects have been enrolled and the futility analysis is completed, up to 15 subjects enrolled subsequently into each treatment arm must consent to and provide both pre-treatment and on-treatment tumor biopsies. Tumor lesions used for biopsy should not be lesions used as RECIST target lesions
6. For dose-escalation and dose-expansion: (If evaluations performed as part of standard of care for other purposes prior to obtaining informed consent are suitable for screening and occurred within 7 days prior to starting treatment, those evaluations do not need to be repeated if the subject consents to their use):
   Adequate organ and marrow function, as defined below:
   • Hemoglobin ≥ 9 g/dL
   • Absolute neutrophil count ≥ 1,500/mm³
   • Platelet count ≥ 100,000/mm³
   • Total bilirubin ≤ 1.5 x ULN except subjects with documented Gilbert's syndrome (> 3 x ULN) or liver metastasis, who must have a baseline total bilirubin ≤ 3.0 mg/dL
   • Alanine aminotransferase (ALT) and AST ≤ 2.5 x ULN; for subjects with hepatic metastases, ALT and AST ≤ 5 x ULN
   • Serum creatinine ≤ 2.0 mg/dL
   • On Day 1, subjects with central nervous system (CNS) metastases must have been treated and must be asymptomatic and meet the following:
     No concurrent treatment, inclusive of but not limited to surgery, radiation, and/or corticosteroids
     • Neurologic stability (lack of signs or symptoms greater than baseline prior to external beam radiation therapy) until the time of dosing of MEDI4736 and MEDI0680
     • For radiation treatment:
       • At least 14 days between last day of stereotactic radiosurgery or gamma-knife treatment and Day 1 of protocol treatment
       • At least 28 days between last day of whole brain radiation therapy and Day 1 of protocol treatment
       • At least 14 days since last dose of corticosteroids and Day 1 of protocol treatment
7. Written informed consent and any locally required authorization (eg, Health Insurance Portability and Accountability Act in the US, European Union [EU] Data Privacy Directive in the EU) obtained from the subject/legal representative prior to performing any protocol-related procedures, including screening evaluations)
8. Female subjects of childbearing potential who are sexually active with a nonsterilized male partner must use at least one highly effective method of contraception from screening and must agree to continue using such precautions for 90 days after the subject's last dose of investigation product. Cessation of contraception after this point should be discussed with a responsible physician. Not engaging in sexual activity for the total duration of the study is an acceptable practice; however, occasional abstinence, the rhythm method, and the withdrawal method are not acceptable methods of contraception. Female subjects should refrain from breastfeeding throughout this period.
   • Females of childbearing potential are defined as those who are not surgically sterile (ie, have not undergone bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or who are not post-menopausal
     • Females < 50 years of age will be considered postmenopausal 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 postmenopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy or hysterectomy).
   • Females ≥ 50 years of age will be considered postmenopausal 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).Highly effective methods of contraception are described in Table 4.1.2-1. A highly effective method of contraception is defined as one that results in a low failure rate (ie, less than 1% per year) when used consistently and correctly. Note that some contraception methods are not considered highly effective (eg male or female condom with or without spermicide; female cap, diaphragm, or sponge with or without spermicide; non-copper containing intrauterine device; progestogen-only oral hormonal contraceptive pills where inhibition of ovulation is not the primary mode of action [excluding Cerazette/desogestrel which is considered highly effective]; and triphasic combined oral contraceptive pills).
9. Nonsterilized males who are sexually active with a female partner of childbearing potential must use male condom plus spermicide from Day 1 through 90 days after the subject's last dose of investigational product. It is highly recommended for a female partner of childbearing potential of a male subject to use a highly effective method of contraception throughout this period, as described in Table 4.1.2-1. In addition, male subjects must refrain from fathering a child or donating sperm while on study and for 90 days after the subject's last dose of investigational product.

Exclusion Criteria

1. Concurrent enrollment in another clinical study, unless in a follow-up period or it is an observational study
2. Subjects with leptomeningeal disease or spinal cord compression are excluded from the study
3. Any concurrent chemotherapy, immunotherapy, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormones for non-cancer-related conditions (eg, insulin for diabetes and hormone replacement therapy) is acceptable (NOTE: Local treatment of isolated lesions for palliative intent is acceptable [eg, by local surgery or radiotherapy])
4. Any investigational anticancer therapy received within 28 days prior to the first dose of MEDI4736 and MEDI0680
5. Any prior ≥ Grade 3 irAE while receiving immunotherapy, including anti-CTLA-4 treatment, or any unresolved irAE > Grade 1
6. Major surgical procedure (as defined by the investigator) within 28 days prior to the first dose of MEDI4736 and MEDI0680 or still recovering from prior surgery
7. Unresolved toxicities from prior anticancer therapy, defined as having not resolved to NCI CTCAE v4.03 Grade 0 or 1 with the exception of alopecia and laboratory values listed per the inclusion criteria. Subjects with prior endocrine toxicities (eg, hypothyroidism) who are stable on replacement therapy are not excluded. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by MEDI4736 and MEDI0680 may be included (eg, hearing loss) after consultation with the medical monitor
8. Current or prior use of immunosuppressive medication within 14 days before the first dose of MEDI4736 and MEDI0680 with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiologic doses not to exceed 10 mg/day of prednisone or equivalent
9. Active or prior documented autoimmune or inflammatory disease (including inflammatory bowel disease, diverticulitis with the exception of diverticulosis, celiac disease, irritable bowel disease; Wegener's granulomatosis; Hashimoto syndrome) within the past 3 years. Subjects with vitiligo, alopecia, Grave's disease, or psoriasis not requiring systemic treatment (within the past 3 years) are not excluded
10. History of primary immunodeficiency or tuberculosis
11. Test results indicating active infection with human immunodeficiency virus (HIV), or hepatitis A, B, or C
12. Receipt of live, attenuated vaccine within 28 days prior to the first dose of MEDI4736 and MEDI0680. NOTE: Subjects, if enrolled, should not receive live vaccine during the study and 90 days after the last dose of MEDI4736 and MEDI0680
13. Females who are pregnant, lactating, or intend to become pregnant during the participation to the study
14. Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, current pneumonitis, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, interstitial lung disease, or psychiatric illness/social situations that would limit compliance with study requirement substantially increase risk of incurring AEs from MEDI4736 or MEDI0680, or compromise the ability of the subject to give written informed consent
15. Other invasive malignancy within 2 years except for noninvasive malignancies such as cervical carcinoma in situ, non-melanomatous carcinoma of the skin or ductal carcinoma in situ of the breast that has/have been surgically cured
16. Known allergy or hypersensitivity to study drug formulations
17. Any condition that, in the opinion of the investigator, would interfere with evaluation of the investigational product or interpretation of subject safety or study results
18. Subjects with advanced NSCLC with tumors harboring anaplastic lymphoma kinase gene rearrangements or epidermal growth-factor receptor-sensitizing mutations who have not received appropriate TKI therapy. These subjects can be enrolled after documented progression or intolerance to appropriate TKIs