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

  • STATUS
    Recruiting
  • End date
    Mar 28, 2023
  • participants needed
    50
  • sponsor
    NeoTX Therapeutics Ltd.
Updated on 16 June 2022
cancer
corticosteroids
white blood cell count
prednisone
systemic therapy
measurable disease
carcinoma
breast cancer
anticoagulants
squamous cell carcinoma
international normalized ratio
kinase inhibitor
prothrombin
corticosteroid
major surgery
cytotoxic chemotherapy
anticoagulant therapy
metastasis
pancreatic adenocarcinoma
brain metastases
pd-l1
medi4736
denosumab
programmed cell death 1 ligand 1
aptt
thromboplastin
durvalumab
cancer treatment
neuropathy
adenocarcinoma
solid tumour
solid tumor
bisphosphonate
triple negative breast cancer
ovarian cancer
metastatic cancer
bisphosphonates
mammogram
squamous cell carcinoma of cervix
head and neck carcinoma
cytotoxic t-lymphocyte antigen 4
diphosphonates
abr-217620
driver mutation

Summary

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.

Description

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.

Details
Condition 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
Treatment Obinutuzumab pretreatment (Gazyva®) Naptumomab estafenatox (ABR-217620; NAP) and durvalumab (IMFINZI; MEDI4736), Naptumomab estafenatox (ABR-217620; NAP) and durvalumab (IMFINZI; MEDI4736)
Clinical Study IdentifierNCT03983954
SponsorNeoTX Therapeutics Ltd.
Last Modified on16 June 2022

Eligibility

Yes No Not Sure

Inclusion Criteria

Must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy
Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Sponsor
All AEs while receiving prior immunotherapy must have completely resolved or resolved to < Grade 1 prior to screening for this study
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 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)

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
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
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: Patients, once enrolled, should not receive live vaccine whilst
receiving study drug and up to 30 days after the last dose of study drug
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
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
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