Tumor, SolidPhase 2NCT03911557
Durvalumab and Tremelimumab Combination in Somatically Hypermutated Recurrent Solid Tumors
A Phase 2 study testing Durvalumab and Tremelimumab in people with Tumor, Solid, run by John L. Villano, MD, PhD at 1 site in United States.
Trial summary
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. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- Tumor, Solid
- What is being tested?
- Durvalumab and Tremelimumab
- Type of treatment
- Injection or infusion
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 14 participants
- Where
- 1 siteUnited States
- Study dates
- 8 Jun 2019to 10 Oct 2025
- Phase
- Phase 2
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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)
- Age >18 years at time of study entry
- Eastern Cooperative Oncology Group (ECOG) performance status of at least 2 and life expectancy greater than 3 months
- Accurate documentation of date of starting previous therapy and date of progression to establish TTP from most recent therapy
- 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:
- Absolute neutrophil count (ANC ≥1.5 (or 1.0) x (> 1500 per mm3)
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- Platelet count ≥100 (or 75) x 109/L (>75,000 per mm3)
- 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.
- 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
- 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
- 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:
- 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)
- 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)
- 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.
- 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
- 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
- Body weight >30 kg
- Cohort specific eligibility requirements:
- 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.
- 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
Who cannot join
- 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
- 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 Study Physician
- 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
- 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
- History of allogenic organ transplantation
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- 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:
- Patients with vitiligo or alopecia
- Patients with hypothyroidism (e.g., following Hashimoto syndrome) stable on hormone replacement
- Any chronic skin condition that does not require systemic therapy
- Patients without active disease in the last 5 years may be included but only after consultation with the study physician
- Patients with celiac disease controlled by diet alone
- 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
- 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 the IP ( durvalumab + tremelimumab combination ) and of low potential risk for recurrence
- Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
- Adequately treated carcinoma in situ without evidence of disease
- History of leptomeningeal carcinomatosis
- 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
- History of active primary immunodeficiency
- 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
- 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:
- Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra articular injection)
- Systemic corticosteroids at physiologic doses not to exceed <<10 mg/day>> of prednisone or its equivalent
- 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
- 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
- Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
- Prior exposure to immune mediated therapy with anti-PD-1/ anti-PDL1including durvalumab therapy combined with an CTLA-4 therapy including tremelimumab
Trial locations and contacts
1 site in 1 country.
About this study
Official title: Phase 2 Investigation of MEDI4736 (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.
Read the detailed description
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.
- Conditions
- Tumor, Solid
- Being tested
- Durvalumab and Tremelimumab
- Keywords
- mutational burden, TMB, PD-1, CTLA-4, MEDI4736, durvalumab, tremelimumab, immune therapy, refractory
- Medical subject headings
- Neoplasms, Diabetes Mellitus, Insulin-Dependent, 12
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Durvalumab and TremelimumabDrug
Durvalumab 1500mg + tremelimumab 75mg via IV infusion Q4W, starting on Week 1, for up to a maximum of 4 doses/cycles followed by durvalumab monotherapy 1500 mg via IV infusion Q4W, starting 4 weeks after the last infusion of the combination, for up to a maximum of 2 years of total therapy.
| Study group | Role | What they receive |
|---|---|---|
| Patients with moderate to high tumor mutational burden | Experimental | Patients with recurrent or refractory disease in solid tumors naïve to anti-PD-1/PD-L1 or anti-CTLA-4 immunotherapy and have moderate to high tumor mutational burden (TMB) Receives: Drug: Durvalumab and Tremelimumab |
What is being measured
The primary outcome is the main question the study is designed to answer.
Time-to-progression ratio (TTP)
The TTP (time-to-progression) ratio is defined for individual patients as the ratio of their TTP on the current therapy to their TTP on the most recent previous therapy
Measured: 2 years (baseline to follow-up)
Secondary outcomes (1)
Progression-free survival
time to progression or death as measured from start of treatment
Measured: 2 years (baseline to follow-up)
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted11 Apr 2019
- Study start8 Jun 2019
- Primary completion10 Oct 2025
- Study completion10 Oct 2025
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Tumor, SolidStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 2
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 14 participants (actual)
Sponsor and investigators
- Lead sponsor
- John L. Villano, MD, PhD
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor-investigator, John L. Villano, MD, PhD, University of Kentucky
- Investigators
- John Villano, MD, Principal investigator, University of Kentucky
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03911557
- Sponsor's protocol ID
- MCC-18-MULTI-25-PMC
- Status last verified
- Nov 2025
- First submitted
- 9 Apr 2019
- Last updated
- 12 Nov 2025
- Results posted
- No
- Data monitoring committee
- Yes
- FDA-regulated drug
- Yes
- FDA-regulated device
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 12 Nov 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Phase 2 Investigation of MEDI4736 (Durvalumab) and Tremelimumab Combination in Somatically Hypermutated Recurrent Solid Tumors
- ClinicalTrials.gov ID
- NCT03911557
- Acronym / sponsor ID
- MCC-18-MULTI-25-PMC
- Conditions
- Tumor, Solid
- Keywords
- mutational burden, TMB, PD-1, CTLA-4, MEDI4736, durvalumab, tremelimumab, immune therapy
- Phase
- Phase 2
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 14 participants (actual)
- Lead sponsor
- John L. Villano, MD, PhDUniversity, hospital or other
- Study start
- 8 Jun 2019 (actual)
- Primary completion
- 10 Oct 2025 (actual)
- Study completion
- 10 Oct 2025 (actual)
- First posted
- 11 Apr 2019 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Detailed description
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Patients with moderate to high tumor mutational burden | Experimental | Drug: Durvalumab and TremelimumabPatients with recurrent or refractory disease in solid tumors naïve to anti-PD-1/PD-L1 or anti-CTLA-4 immunotherapy and have moderate to high tumor mutational burden (TMB) |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (20 listed)
- 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)
- Age >18 years at time of study entry
- Eastern Cooperative Oncology Group (ECOG) performance status of at least 2 and life expectancy greater than 3 months
- Accurate documentation of date of starting previous therapy and date of progression to establish TTP from most recent therapy
- 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:
Key exclusion criteria (28 listed)
- 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
- 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
- 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
- History of allogenic organ transplantation
- 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:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Durvalumab and TremelimumabDurvalumab 1500mg + tremelimumab 75mg via IV infusion Q4W, starting on Week 1, for up to a maximum of 4 doses/cycles followed by durvalumab monotherapy 1500 mg via IV infusion Q4W, starting 4 weeks after the last infusion of the combination, for up to a maximum of 2 years of total therapy. | Drug | Patients with moderate to high tumor mutational burden |
Primary outcome
Time-to-progression ratio (TTP)
Time frame: 2 years (baseline to follow-up)
The TTP (time-to-progression) ratio is defined for individual patients as the ratio of their TTP on the current therapy to their TTP on the most recent previous therapy
1 secondary outcome
Progression-free survival
Time frame: 2 years (baseline to follow-up)
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 12 Nov 2025.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
John Villano, MD principal investigator
University of Kentucky
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 2 study testing Durvalumab and Tremelimumab in people with Tumor, Solid, run by John L. Villano, MD, PhD at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 28 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 12 Nov 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Time-to-progression ratio (TTP) (time frame: 2 years (baseline to follow-up)). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 12 Nov 2025.