Naptumomab Estafenatox in Combination With Durvalumab in Subjects With Selected Advanced or Metastatic Solid Tumors

Naptumomab Estafenatox in Combination With Durvalumab in Subjects With Selected Advanced or Metastatic Solid Tumors

Phase 1B, Open-Label, Dose Escalation and Cohort Expansions Trial of Naptumomab Estafenatox (NAP, ABR-217620) in Combination With Durvalumab (MEDI4736) in Subjects With Selected Advanced or Metastatic Solid Tumors

This is a dose escalation, MTD expansion (Phase 1b) and cohort expansions (Phase 2) study to assess the safety and tolerability of a combination of NAP with durvalumab in subjects with selected advanced or metastatic solid tumors.

This Phase 1b, open-label, multicenter (n=3-5), prospective, dose-finding and MTD cohort expansion study, recruits patients with previously treated solid tumors known with high likelihood of 5T4 antigen expression on tumor cells. Patients in the dose-escalation part are treated with the combination of NAP and durvalumab using a fixed dose of durvalumab and the 3+3 design for NAP dose escalations. The (Maximum Tolerated Dose (MTD) of NAP for the combination treatment will be established based on Dose Limiting Toxicities (DLTs) occurring during the first cycle of the treatment. A second dose escalation part is performed at the second highest safe dose in the dose escalation phase, pre-treated with obinutuzumab (anti-CD20), for elimination of anti-drug antibodies (ADAs) to NAP. In this part, the safety of the NAP-durvalumab combination are assessed with obinutuzumab given prior to the initiation of that regimen. MTD expansion part, in which approximately 10-15 patients are treated at the confirmed MTD of NAP. Ten additional patients are enrolled at the previous dose level to assess whether a lower dose may achieves a better risk-benefit balance. This cohort recruits patients with the same tumor types as in the escalation part, as well as 5T4-positive colorectal cancer (CRC) and gastro-esophageal cancer (GE). Measurable disease is required. This expansion cohort will help assess the biologic activity of the combination and to gain some preliminary insights on its potential antitumor activity. Additional group of approximately 10 patients ("Obi (-7)" group) will be enrolled to test an abbreviated regimen of obinutuzumab pre-treatment. A single infusion of 1000 mg obinutuzumab will be administered on day (-7) prior to initiation of Cycle 1 of the combination of NAP and durvalumab. NAP and durvalumab will be given in the same dose and regimen as in this MTD expansion cohort. The following solid tumors known to have > 80% probability of 5T4 expression and thus may be included in both the dose escalation phase and the MTD expansion: breast cancer, epithelial ovarian cancer, cervical and endometrial cancer, pancreatic cancer, renal and urothelial cancer, head and neck, mesothelioma, melanoma, hepatic carcinoma, prostate cancer, and Non-Small Cell Lung Cancer (NSCLC). Prior PD-1 or PD-L1 therapy is acceptable.

ER+ Breast Cancer, Ovarian Cancer, Cervical Squamous Cell Carcinoma, Pancreatic Adenocarcinoma, Endometrial Cancer, Renal Cell Carcinoma, Urothelial Cancer, Head and Neck Squamous Cell Carcinoma, Mesothelioma, Melanoma, Hepatocellular Carcinoma, Prostate Cancer, NSCLC, HER2-negative Breast Cancer, Triple Negative Breast Cancer, Bladder Cancer, Colorectal Cancer Metastatic, GastroEsophageal Cancer, NSCL2 Gene Mutation

NAP dose-escalation cohorts with a standard 3+3 design. A sentinel patient is recruited at each dose level in the first dose-escalation part. NAP is given for up to 3 cycles in the dose escalation parts and up to 6 cycles in the MTD expansion part.

NAP is to be administered on the first four days of each 21-day cycle, at daily doses of 2 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) will be administered on the second day of each 21-day cycle. After cycle 3, patients will continue to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

NAP is to be administered on the first four days of each 21-day cycle, at daily doses of 5 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) will be administered on the second day of each 21-day cycle. After cycle 3, patients will continue to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

NAP is to be administered on the first four days of each 21-day cycle, at daily doses of 10 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) will be administered on the second day of each 21-day cycle. After cycle 3, patients will continue to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

NAP is to be administered on the first four days of each 21-day cycle, at daily doses of 15 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) will be administered on the second day of each 21-day cycle. After cycle 3, patients will continue to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

NAP is to be administered on the first four days of each 21-day cycle, at daily doses of 15 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) will be administered on the second day of each 21-day cycle. After cycle 3, patients will continue to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Obinutuzumab (1000 mg/day) will be administered on days 13 and 12 prior to the first day of NAP. NAP is to be administered on the first four days of each 21-day cycle, at daily doses of 10 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) will be administered on the second day of each 21-day cycle. After cycle 3, patients will continue to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Obinutuzumab (1000 mg/day) will be administered on days 13 and 12 prior to the first day of NAP. NAP is to be administered on the first four days of each 21-day cycle, at daily doses of 15 µg/kg. Durvalumab (1120 mg, IV, 1- 1.5 hours after completion of the administration of NAP) will be administered on the second day of each 21-day cycle. After cycle 3, patients will continue to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

NAP at 15mcg/kg and durvalumab (1120 mg) will be given for 6 cycles after pre-treatment of obinutuzumab (1000 mg/day) on D-13 and D-12. After cycle 6, patients will continue to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

NAP, at the previous dose level (10mcg/kg), and durvalumab (1120 mg) will be given for 6 cycles after pre-treatment of obinutuzumab (1000 mg/day) on D-13 and D-12. After cycle 6, patients will continue to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

NAP at MTD (10 mcg/kg/day) and durvalumab (1120 mg) will be given for 6 cycles after a single dose of pre-treatment of obinutuzumab (1000 mg/day) on D-7. After cycle 6, patients will continue to receive durvalumab alone at a dose of 1500 mg delivered once every 28 days, until confirmed disease progression or unacceptable toxicity for a maximum of up to 24 months.

Obinutuzumab pretreatment (Gazyva®) Naptumomab estafenatox (ABR-217620; NAP) and durvalumab (IMFINZI; MEDI4736)

Obinutuzumab is given intravenous (I.V.) 1,000 mg concentrate for solution for infusion. NAP is given as an intravenous (I.V.) bolus injection at multiple doses. Durvalumab is given at a dose of 1120 mg, I.V, 1- 1.5 hours after completion of the administration of NAP on the second day of each 21-day cycle, and when administered as monotherapy at a dose of 1500 mg delivered once every 28 days.

NAP is given as an intravenous (I.V.) bolus injection at multiple doses. Durvalumab is given at a dose of 1120 mg, I.V, 1- 1.5 hours after completion of the administration of NAP on the second day of each 21-day cycle, and when administered as monotherapy at a dose of 1500 mg delivered once every 28 days.

The incidence and characteristics of adverse events, associated with ascending doses of NAP in combination with a set dose of durvalumab

Number of participants with infusion reactions (e.g. fever, chills, hypotension, tachycardia etc.), occurrence of any Dose Limiting Toxicity (DLT) during the first cycle of treatment and/or , any clinically significant changes from baseline graded as per NCI Common Toxicity Criteria (CTC).

The incidence and characteristics of adverse events, associated with ascending doses of NAP in combination with a set dose of durvalumab and following pretreatment with obinutuzumab.

Number of participants with infusion reactions (e.g. fever, chills, hypotension, tachycardia etc.), occurrence of any Dose Limiting Toxicity (DLT) during the first cycle of treatment and/or , any clinically significant changes from baseline graded as per NCI Common Toxicity Criteria (CTC).

based on the observed effects of the MTD with additional consideration of all available safety, PK and PD data.

Tumor assessment for ORR, DOR and PFS according to the iRECIST and conventional RECIST 1.1. OS will be based on death events.

From date of initiation of treatment until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 6 months post last patient in.

Assessment of anti-NAP antibody levels and human anti-murine antibody (HAMA) levels at the beginning of each treatment cycle.

From start of treatment till end of cycle 3 in dose escalation and end of cycle 6 in MTD expansion (each cycle is 21 days).

From start of treatment till end of cycle 3 in dose escalation and end of cycle 6 in MTD expansion (each cycle is 21 days).

Inclusion Criteria: Adult at least 18 years of age Histologically and/or cytologically confirmed solid tumor from the following list, that is metastatic/advanced, for which no curative therapy exists: pancreatic adenocarcinoma high-grade serous ovarian cancer cervical squamous cell carcinoma prostate cancer ER+/HER2- or triple-negative breast cancer NSCLC including driver mutation-positive. mesothelioma renal cell carcinoma bladder/urothelial cancer head and neck squamous cell carcinoma melanoma hepatocellular carcinoma endometrial cancer MTD expansion cohort only: 5T4-positive colorectal cancer and 5T4-positive gastroesophageal cancer Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1 a. All patients must provide signed informed consent prior to any study specific procedures that are not part of standard medical care. b. In the MTD expansion, an archival or fresh biopsy will be acceptable at baseline. A second biopsy on Cycle 2 Day 4 is optional for patients who provided a fresh biopsy at baseline. Patients enrolled in the MTD expansion cohort after prior exposure to a checkpoint inhibitor should have a baseline biopsy obtained after completion of the last prior checkpoint inhibitor therapy. Presence of clinically and/or radiologically documented disease. All radiology studies must be performed within 28 days prior to Cycle 1 Day 1 (first NAP treatment day). a. Dose escalation part: patients do not need to have measurable disease by RECIST 1.1 b. MTD dose expansion part: patients must have measurable disease by RECIST 1.1. Previously irradiated lesions may be considered measurable if there has been demonstrated progression in these lesions. Previous therapy: i. All patients must have received at least 1 standard systemic cancer therapy for their tumor type and progressed following their most recent regimen. There is no limit to the number of prior cytotoxic regimens received. ii. Treatment-naïve patients will be eligible only if they refused standard treatment. iii. Patients with prior anti-PD-1, anti PD-L1 or anti CTLA4 therapy are eligible if they have received such therapy for a minimum of 6 months and if they have documented progression of their disease on or off such therapy. Previously treated brain metastases must be asymptomatic without MRI evidence of progression for at least 8 weeks and off steroids for at least 4 weeks before study drug administration to be eligible. At least 21 days since the last chemotherapy, immunotherapy, biological (except for erythropoietin, denosumab and bisphosphonates), and at least 2 weeks from approved tyrosine kinase or mTOR inhibitors therapy and recovery to grade 1 or less (except for alopecia) from any toxicity associated with such treatment. Systemic prednisone therapy ≤10 mg/day or equivalent is acceptable. Higher doses are not acceptable within 1 week prior to start of study treatment and as long as patient is treated with Nap, unless administered to treated Nap-related adverse events. There is no limit on topical, intranasal or inhaled corticosteroids. Prior major surgery completed at least 4 weeks before study drug administration. Adequate hematologic and organ function: WBC ≥3000/μL; neutrophils ≥1500/μL; platelets ≥100,000/μL; hemoglobin ≥9.0 g/dL (may have been transfused); creatinine ≤ 1.5 mg/dL; measured creatinine clearance >40 mL/min or calculated creatinine clearance (CL) > 40, as determined by Cockcroft-Gault (using actual body weight); AST ≤2.5 X ULN; ALT ≤2.5 X ULN (for patients with known liver involvement: AST and ALT ≤5 x ULN).; bilirubin ≤ 1.5 mg/dL (unless diagnosed with Gilbert's syndrome); Coagulation International Normalized Ratio (INR) or Prothrombin Time (PT) and Activated Partial Thromboplastin Time (aPTT) ≤1.5 X ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants. Patients must be willing and able to comply with scheduled visits, drug administration plan, hospitalization for treatment (if needed) and scheduled follow-up visits and examinations as outlined in the protocol, including procedures undertaken to perform fresh tumor biopsies as per protocol Must have a life expectancy of at least 12 weeks Exclusion criteria: Body weight <30kg Patients with a history of other malignancies requiring concurrent anticancer therapy. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [e.g. colitis or Crohn's disease], or other serious gastrointestinal chronic conditions associated with diarrhea), systemic lupus erythematosus, or Wegener syndrome (granulomatosis with polyangiitis), rheumatoid arthritis, uveitis, etc., within the past 2 years prior to the start of treatment. The following are exceptions to this criterion: Patients with Graves' disease, vitiligo or psoriasis not requiring systemic treatment (within the last 2 years). Patients with endocrinopathies (e.g. following Hashimoto syndrome) stable on hormone replacement or do not require any therapy. History of primary immunodeficiency, history of allogenic organ transplant that requires therapeutic immunosuppression and the use of immunosuppressive agents within 28 days of enrollment. NOTE: Intranasal/inhaled corticosteroids or systemic steroids that do not exceed 10 mg/day of prednisone or equivalent dose of an alternative corticosteroid are permissible Patients who have uncontrolled inter-current illness, including but not limited to, ongoing or active infection, symptomatic congestive heart failure, uncontrolled hypertension, unstable angina pectoris, uncontrolled cardiac arrhythmia, active interstitial lung disease, serious chronic gastrointestinal conditions associated with diarrhea, or psychiatric illness/social situations that would limit compliance with study requirement, substantially increase risk of incurring AEs or compromise the ability of the patient to give written informed consent. Recent history of live attenuated vaccine within 30 days prior to the first dose of study drug. NOTE: Patients, once enrolled, should not receive live vaccine whilst receiving study drug and up to 30 days after the last dose of study drug. Known current drug or alcohol abuse Known active or latent tuberculosis (TB) infection (purified protein derivative [PPD] test is not required) as indicated by any of the following: PPD recently converted to positive; chest x-ray with evidence of infections infiltrate. Hepatitis B (known positive HBV surface antigen (HBsAg) result), hepatitis C. 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 (PCR) is negative for HCV RNA. Evidence for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies) Underlying medical conditions that, in the Principal Investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of toxicity determination or adverse events Female patients who are pregnant 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 study treatment (either durvalumab monotherapy or durvalumab + Nap combination therapy). * Highly effective methods of contraception are defined as one that results in a low failure rate (e.g., less than 1% per year) when used consistently and correctly. Note that some contraception methods are not considered highly effective (e.g., 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). Simultaneous participation in any other study involving investigational drugs or having participated in study less than 4 weeks prior to start of study treatment History of leptomeningeal carcinomatosis History of active primary immunodeficiency 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 Sponsor. Patients with irreversible toxicity not reasonably expected to be exacerbated by treatment with Nap or durvalumab (or Obi, in the cohorts receiving Obi pretreatment) may be included only after consultation with the Sponsor. Mean QT interval corrected for heart rate using Fridericia's formula (QTcF) ≥450 ms in male patients, and ≥470 ms in female patients. If the first ECG result is normal, no triplicate test is required. However, any clinically significant abnormalities detected on the 1st ECG will require triplicate ECG result, calculated from 3 ECGs (within 15 minutes at 5 minutes apart) Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients Known hypersensitivity to other recombinant human antibodies Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Local surgery of isolated lesions for palliative intent is acceptable. Patients who have received prior anti-PD-1, anti PD-L1 or anti CTLA-4: Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy. All AEs while receiving prior immunotherapy must have completely resolved or resolved to < Grade 1 prior to screening for this study. Must not have experienced a Grade ≥3 immune-related AE or an immune-related neurologic or ocular AE of any grade while receiving prior immunotherapy. Patients with an endocrine AE of Grade ≤2 are permitted to enroll if they are stably maintained on appropriate replacement therapy and are asymptomatic. Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an immune related AE of any grade if re-challenged, and not currently require maintenance doses of >10 mg prednisone or equivalent per day. Involvement in planning and/or conduct of the study (applies to both sponsor staff and/or staff at the study site). History of progressive multifocal leukoencephalopathy (PML)