| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed/Refractory Multiple Myeloma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed/Refractory Multiple Myeloma |
|
| 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 | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10028228 |
| E.1.2 | Term | Multiple myeloma |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Part 1: To determine safety, tolerability and to establish the
recommended Phase 2 dose (RP2D) of the combination of belantamab
mafodotin and pembrolizumab in subjects with RRMM
Part 2: To assess the clinical activity of the combination treatment with belantamab mafodotin and pembrolizumab in subjects with RRMM |
|
| E.2.2 | Secondary objectives of the trial |
Part 1:
- To evaluate clinical activity of the combination of belantamab mafodotin and pembrolizumab in subjects with RRMM
-To evaluate the pharmacokinetic profile of belantamab mafodotin when administered intravenously in combination with pembrolizumab
-To assess anti-drug antibodies (ADAs) against belantamab mafodotin
Part 2:
-To further evaluate the safety of belantamab mafodotin administered in combination with
pembrolizumab in subjects with RRMM
-To further assess the clinical activity of the combination treatment with belantamab mafodotin and pembrolizumab in subjects with RRMM
-To evaluate the pharmacokinetic profile of belantamab mafodotin when administered intravenously in combination with pembrolizumab
-To assess ADAs against belantamab mafodotin |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Subjects eligible for enrolment in the study must meet all of the following criteria:
1. Provide signed written informed consent, which includes compliance with the
requirements and restrictions listed in the consent form
2. Male or female, 18 years or older (at the time consent is obtained)
3. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
(Appendix 2 of the protocol)
4. Subjects must:
-Has histologically or cytologically confirmed diagnosis of MM, as defined by
IMWG, 2014 [Rajkumar, 2014], and
-Has undergone stem cell transplant or is considered transplant ineligible, and
- Has been treated with at least 3 prior lines of prior anti-myeloma treatments
including an IMiD (eg. lenalidomide or pomalidomide), a proteasome inhibitor
(eg. bortezomib, ixazomib or carfilzomib) and an anti-CD38 antibody alone or
in combination. Line of therapy are defined by consensus panel of the
International Myeloma Workshop [Rajkumar, 2011].
-Has measurable disease defined as one the following:
a) Serum M-protein ≥0.5 g/dL (≥5 g/L)
b) Urine M-protein ≥200 mg/24h
c) Serum FLC assay: Involved FLC level ≥10 mg/dL (≥100 mg/L) and an
abnormal serum free light chain ratio (<0.26 or >1.65)
5. Subjects with a history of autologous stem cell transplant are eligible for study
participation provided the following eligibility criteria are met:
a) transplant was > 100 days prior to study enrolment
b) no active infection (s)
c) subject meets the remainder of the eligibility criteria outlined in this
protocol
6. Adequate organ system functions as defined in Table 3 of the study protocol
7. All prior treatment-related toxicities (defined by National Cancer Institute-
Common Toxicity Criteria for Adverse Events (NCI-CTCAE), version 4.03, 2010)
[NCI, 2010] must be ≤ Grade 1 at the time of enrollment except for alopecia and
Grade 2 neuropathy.
8. A female subject is eligible to participate if she is not pregnant or breastfeeding, and at least one of the following conditions applies:
- Is not a woman of childbearing potential (WOCBP)
OR
-Is a WOCBP and using a contraceptive method that is highly effective (with a
failure rate of <1% per year), preferably with low user dependency, as
described in Appendix 8 during the intervention period and for 9 months after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The
investigator should evaluate the effectiveness of the contraceptive method in
relationship to the first dose of study Intervention. Contraceptive use by women should be consistent with
local regulations regarding the methods of contraception for those
participating in clinical studies.
A WOCBP must have a negative highly sensitive serum pregnancy test (as
required by local regulations) within 72 hours of dosing on C1D1 and
agree to use effective contraception during the study and for 9 months
after the last dose of study medication. Additional requirements for pregnancy testing during and after study intervention are located in Appendix 8 of the protocol.
The investigator is responsible for review of medical history, menstrual history,
and recent sexual activity to decrease the risk for inclusion of a woman with an early undetected pregnancy.
9. Male subjects:
Male subjects are eligible to participate if they agree to the following from the time of first dose of study until 6 months after the last dose of
study treatment to allow for clearance of any altered sperm :
-Refrain from donating sperm
PLUS either:
-Be abstinent from heterosexual intercourse as their preferred and usual
lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent
OR
•Must agree to use contraception/barrier as detailed below
•Agree to use a male condom, even if they have undergone a successful
vasectomy, and female partner to use an additional highly effective
contraceptive method with a failure rate of <1% per year as described in
Appendix 8 when having sexual intercourse with a woman of
childbearing potential who is not currently pregnant.
•Contraceptive use by men should be consistent with local regulations
regarding the methods of contraception for those participating in clinical
studies. |
|
| E.4 | Principal exclusion criteria |
A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. Systemic anti-myeloma therapy or an investigational drug ≤14 days or five half-lives, whichever is shorter, preceding the first dose of study drug
2. Plasmapheresis within 7 days prior to the first dose of study drug
3. Prior treatment with a monoclonal antibody within 30 days of receiving the first dose of study drugs
4. Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti PD-L2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX 40, CD137) and was discontinued from that treatment due to a Grade 3 or higher immune related adverse event (irAE)
5. Current corneal epithelial disease except mild punctate keratopathy
6. Any major surgery within the last four weeks prior to the first dose of study therapy
7. Presence of active renal condition (infection, requirement for dialysis or any other condition that could affect subject’s safety). Subjects with isolated proteinuria resulting from MM are eligible, provided they fulfill criteria given in Table 3 of the protocol
8. Any serious and/or unstable pre-existing medical, psychiatric disorder or other
conditions (including lab abnormalities) that could interfere with subject’s safety,
obtaining informed consent or compliance to the study procedures.
9. Has received prior radiotherapy within 2 weeks of start of study therapy. Subjects must have recovered from all radiation-related toxicities, not requite corticosteroids, and not have had radiation pneumonitis. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) to non-CNS disease.
10. History of (non-infectious) pneumonitis that required steroids, or current pneumonitis
11. Current active liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminemia, esophageal or gastric varices, persistent jaundice, or cirrhosis. Note: Stable chronic liver disease (including Gilbert’s syndrome or asymptomatic gallstones) or hepatobiliary involvement of malignancy is acceptable if subject otherwise meets entry criteria
12. Malignancies other than disease under study are excluded, except for any other malignancy from which the subject has been disease-free for more than 2 years and, in the opinion of the principal investigators and GSK Medical Monitor, will not affect the evaluation of the effects of this clinical trial treatment on the currently targeted malignancy (RRMM). Subjects with curatively treated non-melanoma skin cancer are allowed.
13. Has known active CNS metastases and/or carcinomatous meningitis. Subjects with previously treated brain metastases may participate provided they are radiologically stable, i.e., without evidence of progression for at least 4 weeks by repeat imaging (note that the repeat imaging should be performed during study screening), clinically stable and without requirement of steroid treatment for at least 14 days prior to first dose of study therapy
14. Evidence of cardiovascular risk including any of the following:
a. QTcF interval ≥470 msecs.
NOTE: The QT interval should be corrected for heart rate by Fridericia’s formula (QTcF).
b. Evidence of current clinically significant uncontrolled arrhythmias;
i. including clinically significant ECG abnormalities including 2nd degree
(Type II) or 3rd degree atrioventricular (AV) block.
c. History of myocardial infarction, acute coronary syndromes (including
unstable angina), coronary angioplasty, or stenting or bypass grafting within
six months of Screening.
d. Class III or IV heart failure as defined by the New York Heart Association
functional classification system (Appendix 4 of the protocol)
e. Uncontrolled hypertension
f. Presence of cardiac pacemaker (or defibrillator) with a predominantly
ventricular paced rhythm, limiting ECG/QTcF analysis.
g. Abnormal cardiac valve morphology (≥Grade 2) documented by
echocardiogram (subjects with grade 1 abnormalities [i.e., mild
regurgitation/stenosis] can be entered on study). Subjects with moderate
valvular thickening should not be entered on study.
15. Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to belantamab mafodotin or pembrolizumab, or any of the components of the study treatment.
16. Pregnant or lactating female.
17. Known active infection requiring antibiotic, antiviral, or antifungal treatment.
18. Known HIV infection.
19. Presence of hepatitis B surface antigen (HBsAg), or hepatitis B core antibody (HBcAb at screening or within 3 months prior to first dose of study treatment
Please see the protocol Section 5.2 Exclusion Criteria for a complete list of exclusion criteria
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1:
-Percent of subjects with AEs, changes in clinical signs and laboratory parameters
-Number of subjects with dose limiting toxicities (DLTs)
Part 2:
-Overall Response Rate (ORR), defined as the percentage of subjects with a confirmed PR or better (i.e., PR, VGPR, CR and sCR), according to the IMWG Response Criteria [Kumar, 2016]. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part 1:
-approximately 6 months to reach end of Part 1 Dose Escalation
Part 2:
-at final analysis |
|
| E.5.2 | Secondary end point(s) |
Part 1:
-Overall Response Rate (ORR), defined as the percentage of subjects with a confirmed partial response (PR) or better (i.e., PR, very good partial response [VGPR], complete response [CR] and stringent complete response [sCR]), according to the International Myeloma Working Group (IMWG) Response Criteria [Kumar, 2016].
-Pharmacokinetic parameters following IV administration as data permit (e.g., AUCs, Cmax, time of Cmax [tmax], terminal phase half-life [t½]) after the first dose; concentration at trough (Ctrough), and end of infusion concentration in the subsequent cycles when measured.
-Incidence and titers of ADAs against belantamab mafodotin
Part 2:
-Number (percent) of subjects with AEs, changes in clinical signs and laboratory parameters
-Ocular finding on ophthalmic exam
-Clinical benefit rate (CBR), defined as the percentage of participants with a confirmedminimal response (MR) or better per IMWG
-Duration of response (DoR), defined as: the time from first documented evidence of PR or better, to the time when disease progression (PD) is documented per IMWG; or death due to PD occurs among subjects who achieve an overall response, i.e. confirmed PR or better
-Time to response (TTR), defined as: the time between the date of first dose and the first documented evidence of response (PR or better) among participants who achieved a confirmed response of PR or better
-Time to best response, defined as the time between the date of first dose and the first best documented response (PR or better) among subjects who achieved a confirmed response of PR or better
-Progression-free survival (PFS), defined as: the time from first dose until the earliest date of PD per IMWG, or death due to any cause
-Time to disease progression (TTP), defined as: the time from first dose until the earliest date of PD per IMWG, or death due to PD
-Overall Survival (OS), defined as the time from first dose until death due to any cause
-Pharmacokinetic parameters following IV administration as data permit (e.g., AUCs, Cmax, time of Cmax [tmax], terminal phase half-life [t½]) after the first dose; concentration at trough (Ctrough), and end of infusion concentration in the subsequent cycles when measured.
-Incidence and titer of ADA to belantamab mafodotin |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Secondary endpoints will be evaluated during the dosing schedule under evaluation and at the end of study. For subjects who elect to continue to receive the IMP beyond the dose cohort, all other safety parameters and adverse events are followed until the patient discontinues the study. |
|
| 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 | No |
| 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) | 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| Canada |
| United States |
| Spain |
| Germany |
|
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
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