Durvalumab and Tremelimumab Combination in Somatically Hypermutated Recurrent Solid Tumors
Durvalumab and Tremelimumab Combination in Somatically Hypermutated Recurrent Solid Tumors
This study will examine whether patients with relapsed/refractory solid tumors harboring
 evidence of somatic hypermutation (intermediate versus high tumor mutational burden) will
 exhibit improvement in disease progression-free survival with dual Tremelimumab and
 Durvalumab treatment.
This study is phase II basket trial to evaluate the benefit of immunotherapy (Durvalumab and
 Tremelimumab combination) in treatment of relapse/refractory solid tumor patients whose
 tumors express a high tumor mutational burden (TMB high >20 mutations/MB) or moderate tumor
 mutational burden (10-20 mutations/MB) as based on next generation sequencing (NGS). The
 primary endpoint of the study is the TTP (time-to-progression) ratio or growth modulation
 index (GMI) which is defined for individual patients as the ratio of their TTP on the current
 therapy to their TTP on the most recent previous therapy.
Inclusion Criteria:

 1. Relapsed/refractory solid tumor patients not previously treated with anti-PD-1/PD-L1
 or anti-CTLA-4 immunotherapy whose tumors expressed a high tumor mutational burden
 (TMB) (TMB high >20 mutations/MB) or moderate TMB (10-20 mutations/MB) as based on
 next generation sequencing (NGS)

 2. Age >18 years at time of study entry

 3. Eastern Cooperative Oncology Group (ECOG) performance status of at least 2 and life
 expectancy greater than 3 months

 4. Accurate documentation of date of starting previous therapy and date of progression to
 establish TTP from most recent therapy

 5. Patient must have normal organ and marrow function independent of transfusion for at
 least 7 days prior to screening and independent of growth factor support for at least
 14 days prior to screening as defined below:

 6. Absolute neutrophil count (ANC ≥1.5 (or 1.0) x (> 1500 per mm3)

 7. Platelet count ≥100 (or 75) x 109/L (>75,000 per mm3)

 8. Serum bilirubin ≤1.5 x institutional upper limit of normal (ULN). This will not apply
 to patients with confirmed Gilbert's syndrome, who will be allowed only in
 consultation with their physician.

 9. AST (SGOT)/ALT (SGPT) ≤2.5 x institutional upper limit of normal unless liver
 metastases are present, in which case it must be ≤5x ULN

 10. Measured creatinine clearance (CL) >40 mL/min or Calculated creatinine clearance CL>40
 mL/min by the Cockcroft-Gault formula (Cockcroft and Gault 1976) or by 24-hour urine
 collection for determination of creatinine clearance

 11. The effects of MEDI4736 and tremelimumab on the developing human fetus are unknown.
 Evidence of post-menopausal status or negative urinary or serum pregnancy test for
 female pre-menopausal patients. Women will be considered post-menopausal if they have
 been amenorrheic for 12 months without an alternative medical cause. The following
 age-specific requirements apply:

 12. Women <50 years of age would be considered post-menopausal 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
 post-menopausal range for the institution or underwent surgical sterilization
 (bilateral oophorectomy or hysterectomy)

 13. Women ≥50 years of age would be considered post-menopausal 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)

 14. Females of childbearing potential who are sexually active with a non-sterilized male
 partner must use at least 1 highly effective method of contraception from the time of
 screening and must agree to continue using such precaution for 180 days after the last
 dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose
 of durvalumab monotherapy. Non-sterilized male partners of female patient must use
 male condom plus spermicide throughout this period. Cessation of birth control after
 this point should be discussed with a responsible physician. Not engaging in sexual
 activity for the total duration of the drug treatment and the drug washout period is
 an acceptable practice; however, periodic abstinence, the rhythm method, and the
 withdrawal method are not acceptable methods of birth control. Female patients should
 also refrain from breastfeeding throughout this period.

 15. Non-sterilized males who are sexually active with a female partner of childbearing
 potential must use a male condom plus spermicide from screening through 180 days after
 receipt of the final dose of durvalumab + tremelimumab combination therapy or 90 days
 after receipt of the final dose of durvalumab monotherapy. Not engaging in sexual
 activity is an acceptable practice; however, occasional abstinence, the rhythm method,
 and the withdrawal method are not acceptable methods of contraception. Male patients
 should refrain from sperm donation throughout this period

 16. Patient 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

 17. Body weight >30 kg

 18. Cohort specific eligibility requirements:

 19. Ability to undergo a fresh tumor biopsy for the purpose of screening for this clinical
 trial (including able and willing to give valid written consent) or the ability to
 access an available archival tumor sample taken less than 6 months prior to study
 enrollment if a fresh tumor biopsy is not feasible with an acceptable clinical risk
 and no antecedent treatment has been done.

 20. MSS tumor as documented by either: IHC testing that does not suggest loss of MLH-1,
 MSH-2, PMS2 or MSH6. OR PCR testing that does not suggest MSI

 Exclusion Criteria:

 1. Receipt of the last dose of anticancer therapy (chemotherapy, immunotherapeutic agent,
 endocrine therapy, targeted therapy, biologic therapy, tumor embolization, monoclonal
 antibodies) 30 days prior to the first dose of study drug

 2. 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

 1. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after
 consultation with the Study Physician

 2. Patients with irreversible toxicity not reasonably expected to be exacerbated by
 treatment with durvalumab or tremelimumab may be included only after consultation
 with the Study Physician

 3. Major surgical procedure (as defined by the Investigator) within 28 days prior to the
 first dose of the IP (investigational product, in this study, specifically durvalumab
 + tremelimumab combination). Note: Local surgery of isolated lesions for palliative
 intent is acceptable

 4. History of allogenic organ transplantation

 5. 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], systemic lupus erythematosus, Sarcoidosis syndrome,
 or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid
 arthritis, hypophysitis, uveitis, etc]). The following are exceptions to this
 criterion:

 1. Patients with vitiligo or alopecia

 2. Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on
 hormone replacement

 3. Any chronic skin condition that does not require systemic therapy

 4. Patients without active disease in the last 5 years may be included but only
 after consultation with the study physician

 5. Patients with celiac disease controlled by diet alone

 6. 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, 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

 7. History of another primary malignancy except for

 1. Malignancy treated with curative intent and with no known active disease ≥5 years
 before the first dose of the IP ( durvalumab + tremelimumab combination ) and of
 low potential risk for recurrence

 2. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
 of disease

 3. Adequately treated carcinoma in situ without evidence of disease

 8. History of leptomeningeal carcinomatosis

 9. Patients with untreated brain metastases, spinal cord compression, or leptomeningeal
 carcinomatosis should be excluded from this clinical trial because of their poor
 prognosis, because of symptoms that may arise form inflammatory reactions, and because
 they often develop progressive neurologic dysfunction that would confound the
 evaluation of neurologic and other adverse events. Patients whose brain metastases
 have been treated may participate provided they show radiographic stability (defined
 as 2 brain images, both of which are obtained after treatment to the brain metastases.
 These imaging scans should both be obtained at least four weeks apart and show no
 evidence of intracranial progression). In addition, any neurologic symptoms that
 developed either as a result of the brain metastases or their treatment must have
 resolved or be stable either, without the use of steroids, or are stable on a steroid
 dose of <10mg/day of prednisone or its equivalent and anti-convulsants for at least 14
 days prior to the start of treatment

 10. History of active primary immunodeficiency

 11. Active infection including tuberculosis (clinical evaluation that includes clinical
 history, physical examination and radiographic findings, and TB testing in line with
 local practice), hepatitis B (known positive HBV surface antigen (HBsAg) result),
 hepatitis C, or human immunodeficiency virus (positive HIV 1/2 antibodies). 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 is negative
 for HCV RNA

 12. Current or prior use of immunosuppressive medication within 14 days before the first
 dose of durvalumab or tremelimumab. The following are exceptions to this criterion:

 1. Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra
 articular injection)

 2. Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of
 prednisone or its equivalent

 13. Steroids as premedication for hypersensitivity reactions (e.g., CT scan premedication)
 Receipt of live attenuated vaccine within 30 days prior to the first dose of IP. Note:
 Patients, if enrolled, should not receive live vaccine whilst receiving IP and up to
 30 days after the last dose of IP

 14. 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 durvalumab monotherapy or180 days after
 the last dose of durvalumab + tremelimumab combination therapy

 15. Known allergy or hypersensitivity to any of the study drugs or any of the study drug
 excipients.

 16. Prior exposure to immune mediated therapy with anti-PD-1/ anti-PDL1including
 durvalumab therapy combined with an CTLA-4 therapy including tremelimumab