| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| follicular non-Hodgkin's lymphoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| A specific form of non-Hodgkin's lymphoma |
|
| 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 | LLT |
| E.1.2 | Classification code | 10067070 |
| E.1.2 | Term | Follicular B-cell non-Hodgkin's lymphoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Part 1: Evaluate the safety and tolerability of ascending doses of intratumoral G100 in patients with low-grade NHL receiving local radiation
Part 2: Assess the safety and tolerability of intratumoral G100 or sequential intratumoral G100 and anti-PD-1 therapy in patients with follicular NHL receiving local radiation
Part 3: Evaluate the safety and tolerability of 20 μg/dose of intratumoral G100 in patients with low-grade NHL receiving local radiation
Part 4: Evaluate safety and preliminary clinical efficacy of intratumoral G100 at 20 μg/lesion in single or multiple tumour lesions and pembrolizumab (anti-PD-1) therapy in patients with relapses or refractory follicular NHL who have received at least 3 prior systemic treatments, one of which was or included an anti-CD20 antibody.
Part 5: Evaluate safety and preliminary clinical efficacy of standard induction therapy with rituximab (anti-CD20) in combination with escalating doses of intratumoral G100 in single tumour lesion (etc) |
|
| E.2.2 | Secondary objectives of the trial |
- The nature, frequency and severity of AEs and laboratory abnormalities until 21 days after G100 regimen is completed or discontinued
- Clinical responses by irRC using bi-dimensional measurements and expressed as partial response (PR), complete response (CR), stable disease (SD), or progressive disease (PD), time-to-progression (TTP) and/or progression-free survival (PFS) as a preliminary indication of efficacy
- As an exploratory comparison, assess clinical responses by the International Working Group response criteria for lymphomas (For determining PD, the irRC criteria will be used). Sponsor will assess for clinical responses by the Lugano criteria for lymphomas (Cheson 2014).
- Abscopal tumor responses in non-treated, distal tumour sites |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Follicular low grade NHL, (grades 1, 2, 3A) either treatment naïve or relapsed or refractory following at least one prior treatment. For france, patients with either relapsed or refractory only. In Part 1 Dose Escalation only, in addition to follicular NHL, marginal zone B cell lymphomas: either treatment naïve or relapsed or refractory following at least one prior treatment. In Part 4, enrollment is limited to relapsed or refractory follicular NHL patients who hasve received at least 3 treatments, one of which was or included an anti-CD20 antibody. In Part 5, enrollment will include relapsed or refractory CD20+ follicular NHL following at least one but not more than 2 prior treatments.
2. Tumour mass(es) accessible for intratumoral injection and are being considered for local radiation therapy and at least one additional site of disease outside the radiation field for assessment of distal (abscopal) response (Imaging assisted injections are allowed following approval by Medical Monitor). For Parts 4 and 5, radiation therapy is omitted. Measurable tumour mass(es) accessible for intratumoral injections must be present for treatment and assessment of response.
3. ≥ 18 years of age
4. Life expectancy of ≥ 6 months per the investigator
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
6. ECG without evidence of clinically significant arrhythmia or ischemia
7. If female of childbearing potential (FCBP), willing to undergo pregnancy testing and agrees to use 2 methods of birth control or is considered highly unlikely to conceive during the dosing period and for three months after last study treatment, or if receiving pembrolizumab, four months after last treatment.
8. If male and sexually active with a FCBP, must agree to use effective contraception such as latex condom or is sterile (e.g. following surgical procedure) during the dosing period and for three months after last study treatment, or if receiving pembrolizumab, four months after last treatment |
|
| E.4 | Principal exclusion criteria |
1. Cancer therapies, including chemotherapy, radiation (non-study regimen related), biologics or kinase inhibitors, G-CSF or GM-CSF within 4 weeks prior to the first scheduled G100 dose
2. Investigational therapy within 4 weeks prior to G100 dosing
3. Prior administration of G100 or other intratumoral immunotherapeutics
4. Inadequate organ function including:
a. Marrow: Peripheral blood leukocyte count (WBC) < 3000/mm3, absolute neutrophil count ≤ 1500/mm3, platelets < 75000/mm3, or haemoglobin < 10 gm/dL
b. Hepatic: alanine aminotransferase (ALT), and aspartate aminotransferase (AST) > 2.5 x ULN, total
serum bilirubin > 1.5 x ULN (patients with Gilbert's Disease may be included if their total bilirubin is
≤3.0 mg/dL)
c. Renal: Creatinine > 1.5x ULN
d. Other: INR (prothrombin time ratio) or partial thromboplastin time (PTT) >1.5 x ULN
5. Significant immunosuppression from:
a. Concurrent, recent (≤ 4 weeks ago) or anticipated treatment with systemic corticosteroids at any
dose, or
b. Other immunosuppressive medications such as methotrexate, cyclosporine, azathioprine or
conditions such as common variable hypogammaglobulinemia
6. Pregnant or nursing
7. Myocardial infarction within 6 months of study initiation, active cardiac ischemia or New York
Heart Association (NYHA) Grade III or IV heart failure
8. History of other cancer within 2 years (except non-melanoma cutaneous malignancies and cervical
carcinoma in situ)
9. Recent (< 1 week ago) clinically significant infection, active tuberculosis or evidence of active hepatitis B, hepatitis C or HIV infection
10. Central nervous system involvement with lymphoma, including parenchymal and leptomeningeal disease. In Parts 4 and 5, any involvement with lymphoma in a closed or confined space such as the retroorbital area will need to be pre-approved by the Medical Monitor.
11. Significant autoimmune disease, including active non-infectious pneumonitis, with the exception of alopecia, vitiligo, hypothyroidism or other conditions that have never been clinically active or
were transient and have completely resolved and require no ongoing therapy. (Replacement therapy for hypothyroidism or diabetes is allowed.)
12. Psychiatric, other medical illness or other condition that in the opinion of the PI prevents compliance with study procedures or ability to provide valid informed consent
13. History of significant adverse or allergic reaction to any component of G100 and if enrolled in Part 2, anti-PD-1 antibodies pembrolizumab and/or any of its excipients, and if enrolled in Part 5, anti-CD20 antibodies including rituximab as excipients
14. Use of anti-coagulant agents or history a significant bleeding
diathesis. (If a superficial lymph node or subcutaneous mass is to be
injected, patients on agents such as non-steroidal anti-inflammatory drugs (NSAIDs), aspirin, or clopidogrel are eligible and these agents do not have to be withheld. For procedures with moderate or significant risk of bleeding, long-acting agents such as aspirin or clopidogrel should be discussed with the Medical Monitor and may need to be discontinued before G100 therapy.
For patients enrolled in Part 2 or Part 4 with the potential to receive pembrolizumab:
15. Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis or interstitial lung disease
16. Has received a live virus vaccine within 30 days prior to the first dose of study drug (Applies to patients who may receive either pembrolizumab or rituximab). Examples of live vaccines include, but are not limited to the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guerin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed.
17. Has undergone prior allogeneic hematopoietic stem cell transplantation within the last 5 years. (Subjects who have had a transplant greater than 5 years ago are eligible as long as there are no symptoms of GVHD.)
18. Has had an allogeneic tissue/solid organ transplant
19. Has received prior therapy with an anti-PD-1, anti-programmed death ligand (PD-L)1, or anti-PD-L2 agent or if the patient has previously participated in Merck MK-3475 clinical trials or was previously treated
with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) please refer to the protocol |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1: The nature, frequency and severity of adverse events (AEs) and laboratory abnormalities up through Study Day 28 in patients with low-grade NHL receiving intratumoral G100 and local radiation
Part 2: Assess the nature, frequency and severity of adverse events (AEs) and laboratory abnormalities occurring in patients with follicular NHL receiving local radiation and either intratumoral G100 alone or sequential intratumoral G100 and anti-PD-1 therapy
Part 3: The nature, frequency, and severity of AEs and laboratory abnormalities occurring in patients with follicular NHL receiving local
radiation and G100 at 20 μg/dose
Part 4: The nature, frequency and severity of AEs and laboratory abnormalities and the frequency of clinical responses occurring in patients with follicular NHL receiving intratumoral G100 at 20 μg/lesion in single or multiple tumour masses and pembrolizumab therapy
Part 5: The nature, frequency and severity of AEs and laboratory abnormalities and the frequency of clinical responses occurring in patients with follicular NHL receiving rituximab therapy in combination with escalating doses of intratumoral G100 in single tumour lesions |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1: All AEs and SAEs will be evaluated and reported during visits 2, 5, 6, 7, 8, 9, 10, 10A, 10B, 11, 12; and possibly-related SAEs will be evaluated and reported at follow-up (Day 112) then every 8 weeks
Part 2: All AEs and SAEs will be evaluated and reported during visits 2, 5, 6, 7, 8, 9, 10, 10A, 10B, 11, 12; and possibly-related SAEs will be evaluated and reported during long term follow-up after PD
Part 3: All AEs and SAEs will be evaluated and reported during visits 2, 5,
6, 7, 8, 9, 10, 10A, 10B, 11, 12; and possibly-related SAEs will be
evaluated and reported during long term follow-up after PD |
|
| E.5.2 | Secondary end point(s) |
The nature, frequency and severity of AEs and laboratory abnormalities until 21 days after G100 regimen is completed or discontinued
Assess clinical responses by irRC using bi-dimensional measurements and expressed as partial response (PR), complete response (CR), stable disease (SD), or progressive disease (PD), and time to progression (TTP) as a preliminary indication of efficacy
As an exploratory comparison, assess clinical responses by the International Working Group response criteria for lymphomas. (For determining PD, the irRC criteria will be used.) Sponsor will assess for clinical responses by the Lugano criteria for lymphomas (Cheson 2014).
Assess abscopal tumour responses in non-treated, distal tumour sites |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| See Section 3.2, 3.3 and 3.4 in Protocol IMDZ-G142 for the schedule of events for the secondary endpoints. |
|
| 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 | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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 | Yes |
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
|
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| France |
| Spain |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
|
| 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 | 10 |
| E.8.9.1 | In the Member State concerned days | 16 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 16 |
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