Phase 1 Study of Tremelimumab, Durvalumab, High-dose Chemotherapy, + Autologous Stem Cell Transplant

Eligible subjects were to be enrolled sequentially into one of 4 treatment cohorts (beginning
with Cohort 1) to receive pretreatment with Prevnar-13 on Day -33 ± 2 days, followed by a
single dose of tremelimumab (75 mg) administered either alone (Cohorts 1 and 2) or in
combination with a single dose of durvalumab (1500 mg; Cohorts 3 and 4) on Day -31
(approximately 21 days prior to steady-state leukopheresis for the collection of autologous
peripheral blood lymphocytes [PBLs]). Leukopheresis was performed on Days -10 to -3, followed
by high dose therapy (HDT) comprising melphalan (200 mg/m^2) administered intravenously (IV)
on Day -2, and ASCT using previously banked hematopoietic stem cells on Day 0. Autologous
PBLs were re-infused into subjects on Day +3 following ASCT, with a single dose of
tremelimumab (75 mg) administered on the same day. Following HDT/ASCT, treatment was to
resume with tremelimumab (75 mg) administered either alone (Cohorts 1 and 2) or in
combination with durvalumab (1500 mg; Cohorts 3 and 4) for the first 2 cycles following
HDT/ASCT according to the following schedule.

Late post-ASCT treatment:

- Cohort 1: tremelimumab (75 mg) administered alone on Day 100 (±10) and 4 weeks later
(Cycles 1 and 2)

- Cohort 3: tremelimumab (75 mg) + durvalumab (1500 mg) administered on Day 100 (±10) and
4 weeks later (Cycles 1 and 2)

Early post-ASCT treatment:

- Cohort 2: tremelimumab (75 mg) administered alone on Days 30 through 40 and Day 100
(±10) (Cycles 1 and 2)

- Cohort 4: tremelimumab (75 mg) + durvalumab (1500 mg) administered on Days 30 through 40
and Day 100 (±10) (Cycles 1 and 2)

For Cycles 3 through 8, durvalumab alone (1500 mg every 4 weeks) was to be administered in
all cohorts.

Within each cohort, the second subject did not start treatment until the first subject had
completed early engraftment (approximately Day 12 to 18 post-ASCT); therefore, the first
subject in each cohort received the first dose of tremelimumab ± durvalumab and was observed
for toxicity for approximately 7 weeks prior to enrollment of the second subject.

Protocol-specified dose-limiting toxicities (DLTs) were assessed from the first dose of study
treatment up to and including Cycle 2 dosing (Day 128 for Cohorts 1 and 3 or Day 100 for
Cohorts 2 and 4). Subjects were not to be treated in a new cohort until all subjects in the
previous cohort had completed the DLT evaluation period and ≤ 1 of 6 subjects had experienced
DLT.

After enrollment of 6 subjects in Cohort 1, the study was placed on partial clinical hold by
the Food and Drug Administration (FDA) due to safety signals observed in other studies
investigating pembrolizumab, an anti-programmed cell death-1 (PD-1) antibody, in combination
with immunomodulatory agents in subjects with multiple myeloma. As a result, the single
subject who was receiving durvalumab during Cycles 3 to 8 discontinued study treatment after
Cycle 5; durvalumab was not initiated in the 4 subjects who remained in the study; and no
further subjects were enrolled. Upon recommendations from the two Principal Investigators and
the study chair, the 4 ongoing subjects, who were in the transplant phase of the study, were
permitted to continue post-ASCT tremelimumab treatment after being re-consented under an
intermediate expanded access protocol.

Inclusion Criteria:

1. Histologically confirmed multiple myeloma.

2. Measurable disease either at enrollment, prior to most recent line of salvage therapy,
or prior to most recent line of induction therapy. Measurable disease was defined by
any of the following:

- Serum M-spike ≥ 0.5 g/dL

- Serum free light chain ≥ 10mg/dL

- Urine monoclonal protein ≥ 200 mg/24 hours

- Multifocal plasmacytoma

- ≥ 20% bone marrow plasmacytosis

3. Available CD34+ stem cells (≥ 2 x 10^6/kg).

4. Eligible for autologous stem cell transplantation.

5. Four or less prior lines of systemic therapy for multiple myeloma (induction, first
ASCT, consolidation, and maintenance were considered 1 line of therapy unless
treatment was modified due to progression of disease as defined by International
Myeloma Working Group [IMWG] criteria).

6. Able and willing to provide consent for required bone marrow biopsies.

7. Eastern Cooperative Oncology Group (ECOG) performance status of 0-1.

8. Anticipated lifespan greater than 3 months.

9. Adequate organ function, as defined below:

- Total bilirubin within normal ranges unless associated with hepatobiliary
metastases or Gilbert syndrome, then total bilirubin ≤ 2 x upper limit of normal
(ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN

- Creatinine ≤ 2.0 mg/dL

- Carbon monoxide diffusing capacity (DLCO) ≥ 50%

10. Had been informed of other treatment options.

11. Age ≥ 18 years.

12. Able and willing to give valid written informed consent.

13. Body weight > 30 kg.

Exclusion Criteria:

1. Prior exposure to tremelimumab or durvalumab or other anti-cytotoxic
T-lymphocyte-associated antigen-4 (CTLA-4), anti-PD-1, anti-programmed cell death
ligand-1 (PD-L1) antibodies.

2. History of severe allergic reactions to any unknown allergens or any components of the
study drugs.

3. Active or prior autoimmune disease except for autoimmune thyroiditis, vitiligo, or
psoriasis not requiring systemic therapy.

4. Prior allogeneic transplantation.

5. Any prior Grade ≥ 3 immune-related adverse event (irAE) or any prior
corticosteroid-refractory irAE.

6. Known active or chronic viral hepatitis or history of any type of hepatitis within the
last 6 months.

7. History of sarcoidosis syndrome.

8. Active or history of inflammatory bowel disease (colitis, Crohn's), celiac disease, or
other serious, chronic, gastrointestinal conditions associated with diarrhea. Active
or history of systemic lupus erythematosus or Wegener's granulomatosis.

9. Metastatic disease to the central nervous system for which other therapeutic options,
including radiotherapy, were available.

10. Known immunodeficiency or active human immunodeficiency virus.

11. Other active serious illnesses (e.g., serious infections requiring antibiotics).

12. Prior treatment in any other clinical trial involving another investigational agent
within 4 weeks prior to Day -31 of the study; resolution of respective adverse event
(AE) to Grade 1 or lower should have occurred.

13. Major surgical procedure (as defined by the Investigator) within 30 days prior to Day
-31 or still recovering from prior surgery.

14. Mental impairment that may have compromised the ability to give informed consent and
comply with the requirements of the study.

15. Lack of availability for immunological and clinical follow-up assessments.

16. Women who were breastfeeding or pregnant as evidenced by positive serum pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
[HCG]).

17. Female subjects of childbearing potential who were sexually active with a
nonsterilized male partner must have used at least one highly effective method of
contraception from the time of screening, and must have agreed to continue using such
precautions for 90 days after the last dose of durvalumab or for 6 months after the
last dose of tremelimumab (whichever was longer). Non-sterilized male partners of a
female subject must have used male condoms plus spermicide throughout this period.
Cessation of birth control after this point should have been discussed with a
responsible physician. Not engaging in sexual activity for the total duration of the
trial and the drug washout period was an acceptable practice; however, periodic
abstinence, the rhythm method, and the withdrawal method were not acceptable methods
of birth control.

Female subjects should have refrained from breastfeeding throughout the period
described above.

Females of childbearing potential were defined as those who were not surgically
sterile (i.e., bilateral tubal ligation, bilateral oophorectomy, or complete
hysterectomy) or postmenopausal.

Females were considered post-menopausal if they had been amenorrheic for 12 months
without an alternative medical cause. The following age-specific requirements applied:

- Females < 50 years of age were considered post-menopausal if they had been
amenorrheic for 12 months or more following cessation of exogenous hormonal
treatments and if they had luteinizing hormone and follicle-stimulating hormone
levels in the post-menopausal range for the institution or underwent surgical
sterilization (bilateral oophorectomy or hysterectomy).

- Females ≥ 50 years of age were considered post-menopausal if they had 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).

Women of childbearing potential must have had a negative serum β-HCG pregnancy test
(minimum sensitivity 25 IU/L or equivalent units of HCG) conducted during screening
and a negative urine β-HCG pregnancy test conducted prior to study drug administration
on Day -31. Ongoing serum pregnancy tests were conducted according to the study
protocol.

Nonsterilized male subjects who were sexually active with a female partner of
childbearing potential must have used male condoms plus spermicide from screening
through 90 days after last dose of durvalumab or through 6 months after the last dose
of tremelimumab (whichever was longer). Female partners (of childbearing potential) of
a male subject must have used a highly effective method of contraception throughout
the period described above. Cessation of birth control after this point should have
been discussed with a responsible physician. Not engaging in sexual activity for the
total duration of the trial and the drug washout period was an acceptable practice;
however, periodic abstinence, the rhythm method, and the withdrawal method were not
acceptable methods of contraception.

Male subjects should have refrained from sperm donation throughout this period. A
highly effective method of contraception was defined as one that resulted in a low
failure rate (i.e., less than 1% per year) when used consistently and correctly. Note
that some contraception methods were not considered highly effective (e.g., male or
female condom with or without spermicide; female cap, diaphragm, or sponge with or
without spermicide; non-copper containing intrauterine device; progestogen-only oral
hormonal contraceptive pills where inhibition of ovulation is not the primary mode of
action [excluding Cerazette/desogestrel which was considered highly effective]; and
triphasic combined oral contraceptive pills).

18. Any condition that, in the clinical judgment of the treating physician, was likely to
prevent the subject from complying with any aspect of the protocol or that may have
put the subject at unacceptable risk.

19. Subjects must not have donated blood while on study and for at least 90 days following
the last durvalumab treatment or for 6 months following the last tremelimumab
treatment, whichever was longer.