A total of up to 58 subjects will be enrolled on both phases.
Phase Ib: 6-12 subjects; enrolled into either Cohort 1 or 2. Phase II: 46 subjects; enrolled
into either Cohort 1 or 2.
Cohort 1 (36 subjects): received 0-1 prior therapy and no prior anti-PD-1/PD-L1/CTLA4.
Cohort 2 (16 subjects): received up to 2 prior therapies, one of which must include an
anti-PD-1/PD-L1 therapy to which they did not respond. Only one prior anti-PD-1/PD-L1 therapy
Patients from Phase Ib treated at the eventual phase II dose will be combined with patients
in Phase II in the efficacy analysis.
- Therapy will start with guadecitabine on days 1-5 of a 28-day cycle. Guadecitabine will
be dosed subcutaneously on days 1-5 at either dose level 0 (60 mg/m2) or dose level -1
(45 mg/m2), based on the recommended phase II dose.
- Durvalumab will be started on day 8 of the 28-day cycle. Durvalumab will be administered
intravenously at a flat dose of 1500mg every 28 days.
- Study treatment may continue for up to 13 cycles (52 weeks) in the absence of confirmed
progression, intolerable toxicity, or withdrawal of consent.
Phase Ib Treatment Plan
- Dose limiting toxicities (DLTs) will be evaluated within the first cycle (i.e., within
the first 28 days).
- Six patients will be enrolled at dose level 0. If 2 or fewer patients experience a dose
limiting toxicity, the study will continue to the phase II portion at dose level 0.
- Alternately, if 3 or more patients have a dose limiting toxicity at dose level 0, 6
patients will be accrued at the lower dose (dose -1). If 2 or fewer patients experience
a dose limiting toxicity, the study will continue to phase II at dose level -1.
- If 3 or more subjects experience a dose limiting toxicity at dose level -1, the
treatment will be considered unsafe and the trial will be stopped. In this case,
durvalumab and guadecitabine will be permanently discontinued and the subjects followed
Subject must meet all of the following applicable inclusion criteria to participate in this
- Written informed consent and HIPAA authorization for release of personal health
- ECOG Performance Status 0-1 within 28 days prior to registration.
- Histological diagnosis of clear cell renal cell carcinoma (pure or mixed) with
radiologic or histologic evidence of metastatic disease.
- At least 1 lesion, not previously irradiated that can be accurately measured at
baseline as ≥ 10 mm in the longest diameter (except lymph nodes which must have a
short axis ≥ 15mm) with a computed tomography (CT) or magnetic resonance imaging (MRI)
and that is suitable for accurate repeated measurements as per Response Evaluation
Criteria in Solid Tumors, version 1.1 (RECIST 1.1) guidelines.
- For cohort 1, subjects may have received up to 1 and no more than 1 prior line of
systemic therapy (not counting any neoadjuvant/adjuvant therapy) including anti-VEGF,
VEGFR inhibitor, MET inhibitor or mTOR inhibitor for metastatic disease. They cannot
have received any prior anti-PD-1/PD-L1/CTLA4 therapy including durvalumab.
- For cohort 2, subjects may have received up to 2 prior systemic therapies which should
include 1 (and only 1) prior anti-PD-1/PD-L1 therapy but did not have an objective
response to the prior anti-PD-1/Pd-L1 therapy. The treating investigator must document
that the patient did not have an objective response to prior anti-PD-1/PD-L1 therapy.
They may have received prior anti-CTLA4 therapy.
- Subjects may not have had 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.
- Prior cancer treatment must be completed at least 14 days prior to study registration
and the subject must have recovered from all reversible acute toxic effects of the
regimen (other than alopecia) to ≤Grade 1 or baseline.
- Demonstrate adequate organ function as defined in the table below; all screening labs
to be obtained within 28 days prior to registration:
- White blood cell (WBC) ≥ 3 K/mm^3
- Absolute Neutrophil Count (ANC) ≥ 1.5 K/mm^3
- Hemoglobin (Hgb) ≥ 9 g/dL
- Platelets (Plt) ≥ 100,000/mm^3
- Calculated creatinine clearance ≥ 40 cc/min using the Cockcroft-Gault formula
- Total Bilirubin ≤ 1.5 × upper limit of normal (ULN), except in cases of Gilbert's
syndrome where the criteria will be ≤ 5 x ULN
- Aspartate aminotransferase (AST) ≤ 2.5 × ULN
- Alanine aminotransferase (ALT) ≤ 2.5 × ULN
- Females of childbearing potential must have a negative serum pregnancy test
within 28 days prior to registration.
- Females of childbearing potential and males must be willing to abstain from
heterosexual activity or to use at least 1 highly effective methods of
contraception from the time of informed consent until 30 days after treatment
discontinuation. The two contraception methods can be comprised of two barrier
methods, or a barrier method plus a hormonal method.
- Life expectancy ≥ 12 weeks (in the opinion of the Investigator)
- Body weight >30kg
- Subject 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.
Subjects meeting any of the criteria below may not participate in the study:
- Active infection requiring systemic therapy.
- Brain metastases or spinal cord compression. Patients with suspected brain metastases
at screening should have an MRI (preferred) or CT each preferably with IV contrast of
the brain prior to study entry. Patients whose brain metastases have been treated may
be considered if they have completed their treatment for brain metastasis at least 4
weeks prior to study registration provided they show radiographic stability (defined
as 1 brain image, obtained after treatment to the brain metastases). In addition, any
neurologic symptoms that developed either as a result of the brain metastases or their
treatment must have resolved or be stable without the use of steroids for at least 14
days prior to the start of treatment.
- Pregnant or breastfeeding
- 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 IP and of low potential risk for recurrence.
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
- Adequately treated carcinoma in situ without evidence of disease.
- Treatment with any investigational drug within 14 days prior to study registration.
- 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], celiac disease, irritable bowel disease, or other
serious gastrointestinal chronic conditions associated with diarrhea, systemic lupus
erythematosus, sarcoidosis syndrome, or Wegener syndrome [granulomatosis with
polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc])
within the last 3 years prior to study registration. The following are exceptions to
this criterion: The following are exceptions to this criterion:
- Subjects with vitiligo or alopecia.
- Subjects with hypothyroidism (eg, following Hashimoto syndrome) stable on hormone
- Any chronic skin condition that does not require systemic therapy.
- Subjects without active disease in the last 5 years may be included but only
after consultation with the study physician.
- Subjects with celiac disease controlled by diet alone.
- Current or prior use of immunosuppressive medication within 28 days before the first
dose of durvalumab, with the exceptions of intranasal and inhaled corticosteroids or
systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of
prednisone, or an equivalent corticosteroid. The following are exceptions to this
- Intranasal, inhaled, topical steroids, or local steroid injections (eg, intra
- Systemic corticosteroids at physiologic doses not to exceed 10 mg/day of
prednisone or its equivalent.
- Steroids as premedication for hypersensitivity reactions (eg, CT scan
- Involvement in the planning and/or conduct of the study (applies to both AstraZeneca/
MedImmune staff and/or staff at the study site).
- Concurrent enrollment in another clinical study, unless it is an observational
(non-interventional) clinical study or during the follow-up period of an
- Any concurrent chemotherapy, biologic or hormonal therapy for cancer treatment.
Concurrent use of hormonal therapy for non-cancer-related conditions (e.g. hormone
replacement therapy) is acceptable. Note: Local treatment of isolated lesions,
excluding target lesions, for palliative intent is acceptable (e.g., local surgery or
- Major surgical procedure (as defined by the Investigator) within 28 days prior to
study registration. Note: local surgery of isolated lesions for palliative intent is
- History of allogenic organ transplantation that requires use of immunosuppressive
- 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, 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.
- History of leptomeningeal carcinomatosis.
- Active infection including tuberculosis (clinical evaluation that includes clinical
history, physical examination and radiographic findings), hepatitis B (known positive
HBV surface antigen (HBsAg) result), hepatitis C, or human immunodeficiency virus
(positive HIV 1/2 antibodies). Subjects with a past or resolved HBV infection (defined
as the presence of hepatitis B core antibody [anti-HBc] and absence of HBsAg) are
eligible. Subjects positive for hepatitis C (HCV) antibody are eligible only if
polymerase chain reaction is negative for HCV RNA.
- Receipt of live attenuated vaccine within 30 days prior to the first dose of study
drug. Note: patients, if enrolled, should not receive live vaccine during the study
and up to 30 days after the last dose of study drug.
- 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 drug.
- Known allergy or hypersensitivity to study drugs or other humanized monoclonal
- Patient ≤30kg in weight.
- Mean QT interval corrected for heart rate (QTc) ≥470 ms calculated from 3
electrocardiograms (ECGs) using Fridericia's Correction.
- 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
- Subjects with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
consultation with the Study Physician.
- Subjects with irreversible toxicity not reasonably expected to be exacerbated by
treatment with durvalumab may be included only after consultation with the Study
- Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required
steroid treatment, or any evidence of clinically active interstitial lung disease.