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, will accrue patients with previously treated solid tumors known with high
likelihood of 5T4 antigen expression on tumor cells.
Patients in the dose-escalation part will be 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 will be
assessed with obinutuzumab given prior to the initiation of that regimen. If safety and
successful elimination of ADAs is confirmed, pretreatment with obinutuzumab will be tested
further in the MTD expansion cohort.
MTD expansion part, in which 10-15 patients will be treated at the confirmed MTD of NAP. This
cohort will accrue 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,
available tumor deposit and repeat biopsy are required. This expansion cohort will help
assess the biologic activity of the combination and to gain some preliminary insights on its
potential antitumor activity.
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.
Inclusion Criteria:
1. Adult at least 18 years of age
2. Histologically and/or cytologically confirmed solid tumor from the following list,
that is metastatic/advanced, for which no curative therapy exists:
1. pancreatic adenocarcinoma
2. high-grade serous ovarian cancer
3. cervical squamous cell carcinoma
4. prostate cancer
5. ER+/HER2- or triple-negative breast cancer
6. NSCLC including driver mutation-positive.
7. mesothelioma
8. renal cell carcinoma
9. bladder/urothelial cancer
10. head and neck squamous cell carcinoma
11. melanoma
12. hepatocellular carcinoma
13. endometrial cancer
14. MTD expansion cohort only: 5T4-positive colorectal cancer and 5T4-positive
gastroesophageal cancer
3. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
4. a. All patients must provide signed informed consent prior to any study specific
procedures that are not part of standard medical care.
b. Patients in the MTD expansion cohort must also provide their consent to undergo 2
tumor biopsies: one prior to treatment (during screening) and the second on cycle 1
day 4. An archival biopsy will be acceptable as baseline biopsy if it was collected
within the 3 months preceding screening. Otherwise, a fresh biopsy is required.
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.
5. Presence of clinically and/or radiologically documented disease. All radiology studies
must be performed within 28 days prior to subject enrolment (subject enrolment=Day 1)
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 and at
least one additional accessible lesion for biopsy. Previously irradiated lesions may
be considered measurable if there has been demonstrated progression in these lesions.
6. 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.
7. 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.
8. 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.
9. 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.
10. Prior major surgery completed at least 4 weeks before study drug administration.
11. 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.
12. 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
13. Must have a life expectancy of at least 12 weeks
Exclusion criteria:
1. Body weight <30kg
2. Patients with a history of other malignancies requiring concurrent anticancer therapy.
3. 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:
1. Patients with Graves' disease, vitiligo or psoriasis not requiring systemic
treatment (within the last 2 years).
2. Patients with endocrinopathies (e.g. following Hashimoto syndrome) stable on
hormone replacement or do not require any therapy.
4. 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
5. 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.
6. 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.
7. Known current drug or alcohol abuse
8. 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.
9. 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.
10. Evidence for human immunodeficiency virus (HIV) (positive HIV 1/2 antibodies)
11. 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
12. 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).
13. Simultaneous participation in any other study involving investigational drugs or
having participated in study less than 4 weeks prior to start of study treatment
14. History of leptomeningeal carcinomatosis
15. History of active primary immunodeficiency
16. 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
17. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Sponsor.
18. 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.
19. 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)
20. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
excipients
21. Known hypersensitivity to other recombinant human antibodies
22. 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.
23. 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.
24. Involvement in planning and/or conduct of the study (applies to both sponsor staff
and/or staff at the study site).
25. History of progressive multifocal leukoencephalopathy (PML)
