| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Metastatic colorectal adenocarcinoma (without microsatellite instability (not MSI)), triple negative breast cancer, prostate adenocarcinoma, stomach and esophageal gastric junction adenocarcinoma and human papilloma virus (HPV) negative head and neck squamous cell carcinoma with detection of ≥ 5 somatic mutations per megabase measured by whole exome sequencing in a tumor sample of the patient |
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| E.1.1.1 | Medical condition in easily understood language |
| Metastatic colorectal adenocarcinoma, breast cancer, prostate adenocarcinoma, stomach and esophageal gastric junction adenocarcinoma and HPV negative head and neck squamous cell carcinoma |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10052360 |
| E.1.2 | Term | Colorectal adenocarcinoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10075566 |
| E.1.2 | Term | Triple negative breast cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10066350 |
| E.1.2 | Term | Adenocarcinoma of the gastrooesophageal junction |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060121 |
| E.1.2 | Term | Squamous cell carcinoma of head and neck |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10060862 |
| E.1.2 | Term | Prostate cancer |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine the efficacy (as measured by overall tumour response rate) of the combination of durvalumab and tremelimumab when given to previously treated patients with solid tumors harboring a high mutational load. |
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| E.2.2 | Secondary objectives of the trial |
1. To determine overall survival (OS) and disease free survival (DFS).
2. To determine the complete response (CR) rate among cohorts as well as the disease control (DC) at 12 weeks and at the end of the study.
3. To determine the duration of response among each cohort (DoR)
4. To assess safety of this therapy.
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Written informed consent obtained from the subject prior to performing any protocol-related procedures, including screening evaluations
2. Age ≥ 18 years
3. Histologically confirmed diagnosis of metastatic colorectal adenocarcinoma (without microsatellite instability (not MSI), triple negative breast cancer, prostate adenocarcinoma, stomach and esophageal gastric junction adenocarcinoma and human papilloma virus (HPV) negative head and neck squamous cell carcinoma.
4. No standard treatment available or standard treatment refused
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1 with no deterioration over the 2 weeks prior to starting dose
6. Estimated life expectancy of greater than 12 weeks
7. Detection of ≥ 5 somatic mutations per megabase measured by whole exome sequencing in a tumor sample of the patient taken after completing last therapy, within a molecular screening program (this data must been known before screening period)
8. Total bilirubin ≤ 1.5 ULN (for subjects with documented/suspected Gilbert’s disease, bilirubin ≤ 3 × ULN), ALT or AST ≤ 2.5 ULN (for subjects with liver metastases, AST or ALT ≤ 5 × ULN), albumin ≥ 30 g/L
9. Haemoglobin > 9 g/dL, neutrophils > 1500/mm3, platelets > 100,000/mm3
10. Serum creatinine 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. At least one lesion, not previously irradiated, that may be measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥ 15 mm) with computed tomography (CT) or magnetic resonance imaging (MRI) and suitable for repeated assessment according to Response Evaluation Criteria in Solid Tumors (RECIST) guidelines v1.1.
12. 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 screening, and must agree to continue using such precautions for 180 days after the final dose of durvalumab and tremelimumab or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period; cessation of birth control after this point should be discussed with a responsible physician. Male partners of a female subject must use male condom plus spermicide throughout this period. 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.
a. Females of childbearing potential are defined as those who are not surgically sterile (ie, bilateral tubal ligation, bilateral oophorectomy, or complete hysterectomy) or postmenopausal (defined as 12 months with no menses without an alternative medical cause)
b. Subjects must use at least one method of contraception highly effective, such as Copper T intrauterine device, Levonorgestrel-releasing intrauterine system (eg, Mirena® ) a Etonogestrel implants; eg, Implanon or Norplan, Intravaginal device; eg, ethinylestradiol and etonogestrel, Medroxyprogesterone injection: Depo-Provera, Normal and low dose combined oral contraceptive pil, Norelgestromin/ethinylestradiol transdermal system or use of Cerazette (desogestrel)
c. Female subjects should also refrain from breastfeeding throughout this period
d. Females of childbearing potential must have a negative serum pregnancy test result within 3 days prior to initiation of study drugs
Nonsterilized males who are sexually active with a female partner of childbearing potential must use a male condom with spermicide for 180 days after the final dose of durvalumab and tremelimumab or 90 days after the last dose of durvalumab monotherapy, whichever is the longer time period. Female partners of a male subject must use a highly effective method of contraception throughout this period. 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 subjects should refrain from sperm donation and female subjects should refrain from oocyte donation throughout this period.
13. Absence of any psychological, familial, sociological or geographical condition potentially hampering compliance with the study protocol and follow-up schedule; those conditions should be discussed with the patient before inclusion in the trial
14. 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.
15. Patient must be affiliated to a social security system or beneficiary of the same
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| E.4 | Principal exclusion criteria |
3. Any previous treatment with immunotherapy including (but not limited to) compounds such as, PD1 or PD-L1 inhibitors, including durvalumab or an anti-CTLA4 inhibitors, including tremelimumab.
4. Previous exposure to anti oncogenic vaccines, such as Sipuleucel – T is not allowed
5. History of another primary malignancy except for:
a. Malignancy treated with curative intent and with no known active disease ≥5 years before the first dose of study drug and of low potential risk for recurrence
b. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease
c. Adequately treated carcinoma in situ without evidence of disease eg, cervical cancer in situ.
6. Receipt of the last dose of anti-cancer therapy 28 days prior to the first dose of study drug. A shorter duration of five half times may be considered after Sponsor approval, for patients treated with non-cytotoxic drugs.
7. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or tremelimumab.
8. 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
a. Patients with Grade ≥2 neuropathy will be evaluated on a case-by-case basis after consultation with the Study Physician.
b. 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.
9. Any concurrent chemotherapy, IMP, biologic, or hormonal therapy for cancer treatment. Concurrent use of hormonal therapy for non-cancer-related conditions (eg, hormone replacement therapy) is acceptable.
10. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IMP. Note: Local surgery of isolated lesions for palliative intent is acceptable.
11. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], diverticulitis [with the exception of diverticulosis], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]).
12. History of primary immunodeficiency
13. History of allogeneic organ transplant
14. 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
15. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
16. Active infection including tuberculosis, hepatitis B , 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.
17. History of leptomeningeal carcinomatosis
18. Subjects with uncontrolled seizures
19. Brain metastases or spinal cord compression unless the patient is stable (asymptomatic; no evidence of new or emerging brain metastases; and stable and off steroids for at least 28 days prior to start of study treatment). Following radiotherapy and/or surgery of the brain metastases patients must wait 4 weeks following the intervention and before randomisation with imaging to confirm stability.
20. Receipt of live attenuated vaccine within 30 days prior to the first dose of IMPs. Note: Patients, if enrolled, should not receive live vaccine whilst receiving IMPs and up to 30 days after the last dose of IMPs.
21. 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 180 days after the last dose of durvalumab + tremelimumab combination therapy or 90 days after the last dose of durvalumab monotherapy or confirmation of PD and investigator determination that the subject is no longer benefiting from treatment with durvalumab + tremelimumab whichever is the longer time period.
22. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Objective tumour response (both complete and partial response) will be measured according to RECIST (version 1.1) at 12 weeks |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
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| E.5.2 | Secondary end point(s) |
Disease control rate (DCR) is the proportion of patients with complete response (CR), partial response (PR), or stable disease (SD) measured by RECIST criteria v1.1 guidelines (including disease control at 12 weeks).
Duration of response (DoR) is the time calculated from the documentation of tumor response to disease progression.
Progression free survival (PFS) is defined as the time from the first day of study treatment to the date of the first documented tumor progression or death due to any cause, whichever occurs first. Subjects who did not progress or die will be censored on the date of their last evaluable tumor assessment.
Overall survival (OS) is the time from the first day of study treatment with durvalumab and tremelimumab to the date of death due to any cause. A subject who has not died will be censored at last known date alive.
Safety will be evaluated according to NCI CTCAE classification.
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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