Overexpression of activation-induced cytidine deaminase (AID) or other cytidine deaminases
causes high rates of deoxyribonucleic acid (DNA) damage (mutations, double strand DNA breaks,
and chromosome rearrangements) in a high number of patients with B-cell malignancies, such as
NHL, MM, and CLL, and in a subset of patients with solid tumors, such as non-small cell lung
cancer (NSCLC), sarcoma, breast cancer, ovarian cancer, and squamous cell carcinoma of the
head and neck. Cancer cells that overexpress AID and other cytidine deaminases rely on RAD51,
a protein involved in homologous recombination, to repair the DNA damage caused by cytidine
deaminases. Inhibition of RAD51 with CYT-0851 in preclinical models induces cell death, tumor
growth delay or tumor regression.
The Phase 1 part of the study will follow an accelerated titration design, which includes
enrollment of single patient cohorts until certain criteria are met, followed by a standard
3+3 design. This design will allow for identification of a recommended phase 2 dose (RP2D)
level while dosing the least number of patients as possible at potentially sub-therapeutic
doses. Upon identification of the RP2D in the monotherapy, the study will open to three
combination treatment arms to identify the RP2D in combination with rituximab and
bendamustine in Non-Hodgkin Lymphoma and capecitabine or gemcitabine for solid tumors. In the
Phase 2 part of the study, preliminary efficacy will be evaluated in 8 expansion cohorts
(total n = 92-220), using a Simon two-stage design. The RP2D will be selected based on the
MTD, the safety profile, PK, and available pharmacodynamics data generated from all subjects
in Phase 1.
In both Phase 1 and Phase 2, patients will be treated in continuous 21-day or 28-day cycles
and all patients will be assessed for response every 2 cycles. Treatment will be terminated
if the patient progresses, cannot tolerate treatment, or withdraws consent from active
therapy. Patients will undergo a safety evaluation approximately 1 month (28-35 days) after
the last dose. Patients will be followed for response until progression is documented.
Key Phase 1 Inclusion Criteria
1. Male or female ≥18 years of age at time of informed consent.
1. Female subjects of childbearing potential must be non-lactating, not pregnant as
confirmed by a negative serum pregnancy test at most 30 days before enrollment
and within 72 hours before the first administration of CYT-0851
2. Female subjects of childbearing potential must not donate ova during the study
and for at least 90 days after the last dose of study drug and must agree to
continue using an effective method of contraception during the screening period
to first study drug administration until 90 days after the last dose of study
drug
3. Male subjects who have not had a vasectomy must agree to use an effective method
of contraception during the study and until 90 days after the last dose of the
study drug, and to not donate sperm during the study and for at least 90 days
after the last dose of study drug
2. ECOG Performance Status of 0-1
3. Measurable disease defined by disease-specific response criteria
4. Histologically-proven B cell malignancies, meeting the following criteria:
1. Relapsed, refractory B-cell non-Hodgkin lymphoma requiring therapy, after at
least two prior therapies, and if transplanted, then at least 3-month post
autologous stem cell transplant and if CART-treated, then evidence of progression
no sooner than 3 months post CART treatment, or
2. Relapsed, refractory chronic lymphocytic leukemia requiring therapy after at
least two prior therapies, including BTK and BCL-2 inhibitor therapy (unless
ineligible for such therapy), or
3. For multiple myeloma, relapsed or progressive on or after treatment with at least
three prior therapies that included a proteasome inhibitor, an imide,
daratumumab, and if transplant eligible, a bone marrow transplant (unless unfit
for transplant), or
5. Histologically-proven solid tumor meeting the following criteria:
1. Patients must have failed, refused, or not be eligible for further standard
therapies (including chemotherapy, hormonal therapies, Her-2 directed therapies,
as appropriate) expected to provide clinical benefit, and meeting the following
criteria
2. Metastatic breast cancer (including ER/PR positive or negative, Her-2 positive
and negative, triple negative), treated with at least 1 prior therapy for
metastatic disease, or
3. Recurrent squamous cell carcinoma of the head and neck (HNSCC) (dose escalation)
or human papilloma virus positive (HPV+) HNSCC (dose-escalation and backfill),
treated with at least 1 prior therapy, or
4. Ovarian cancer, progressive after treatment with at least prior platinum-based
chemotherapy, and therapy with a PARP inhibitor or
5. Soft tissue sarcoma, treated with at least one line of prior systemic therapy, or
6. Recurrent metastatic or locally advanced pancreatic cancer after first line
chemotherapy (backfill patients only) or
7. Histologically-proven advanced small-cell lung cancer (SCLC) (backfill patients
only).
1. Patients with mixed histology are not allowed
2. Prior treatment with platinum containing chemotherapy regimen with no
evidence of progression within 90 days of last dose of platinum agent and
anti-PD-(L)1 unless contraindicated
3. At least 1 prior line of chemotherapy, but no more than 3 prior lines of
therapy
6. Understands the procedures and requirements of the study and provides written informed
consent and authorization for protected health information disclosure
7. Willing and able to comply with the requirements of the study protocol
8. Site of disease amenable to a biopsy and willing to undergo biopsy required for
backfill, or for dose-escalation if considered unsafe (approval to participate in the
study required by the Medical Monitor) provide an archival sample ≤ 12 months old
Key Phase 2 Inclusion Criteria
1. Male or female ≥18 years of age at time of informed consent.
1. Female subjects of childbearing potential must be non-lactating, not pregnant as
confirmed by a negative serum pregnancy test at most 30 days before enrollment
and within 72 hours before the first administration of CYT-0851
2. Female subjects of childbearing potential must not donate ova during the study
and for at least 90 days after the last dose of study drug and must agree to
continue using, an effective method of contraception during the screening period
to first study drug administration until 90 days after the last dose of study
drug
3. Male subjects who have not had a vasectomy must agree to use an effective method
of contraception during the study and until 90 days after the last dose of the
study drug, and to not donate sperm during the study and for at least 90 days
after the last dose of study drug
2. ECOG Performance Status of 0-1
3. Measurable disease defined by disease-specific response criteria
4. Site of disease amenable to a biopsy and willing to undergo a biopsy for the
determination of biomarker status, or, if considered unsafe (approval to participate
in the study required by the Medical Monitor), archival sample ≤ 12 months old for
determination of biomarker status.
5. Biomarker positive on recent biopsy or bone marrow sample if required for the specific
cohort.
6. Histologically-proven B cell malignancies, meeting the following criteria:
1. DLBCL Cohort
1. Histologically-documented DLBCL or double hit lymphoma (B-cell lymphoma,
unclassifiable, with features intermediate between diffuse large B-cell
lymphoma and Burkitt lymphoma with BCL2 and MYC translocations (WHO
Classification)
2. Progressing on or after treatment with at least two prior lines of therapy,
including R-CHOP or equivalent first line therapy
3. If transplanted, then at least 3-month post autologous stem cell transplant
4. If CART-treated, then evidence of progression no sooner than 3 months post
CART treatment
2. MCL Cohort
1. Histologically-documented MCL
2. Any stage at diagnosis
3. Progressing on or after treatment with at least 2 prior lines of therapy,
including a Bruton tyrosine kinase (BTK) inhibitor, after a 14-day washout
period
3. Multiple Myeloma Cohort 1) Relapsed or progressing after treatment with at least
3 prior therapies that include a proteasome inhibitor, an Immunomodulatory imide
drug (IMiD), daratumumab, and, if transplant eligible, a bone marrow transplant
(unless unfit for transplant)
7. Or Histologically-proven solid tumors meeting the following criterial
1. Patients must have failed, refused, or not be eligible for further standard
therapies (including chemotherapy, hormonal therapies, Her-2 directed therapies,
as appropriate) expected to provide clinical benefit, and meeting the following
criteria
2. Triple Negative Breast Cancer Cohort
1. Histologically-documented triple negative breast cancer, ER/PR negative
(defined as <10% of cells expressing hormonal receptors via
immunohistochemistry (IHC) analysis), and HER2-negative, defined as either
of the following by local laboratory assessment:
- In situ hybridization (ISH) non-amplified (ratio of HER2 to CEP17 < 2.0
or single probe average HER2 gene copy number < 4 signals/cell), or
- IHC 0 or IHC 1+
2. At least 1 prior line of chemotherapy, but no more than 5 prior lines of
chemotherapy
3. Ovarian Cancer Cohort
1. Histologically-proven metastatic epithelial ovarian cancer
2. Prior treatment with a platinum containing chemotherapy regimen
3. Prior treatment with PARP inhibitor, and, unless in adjuvant setting,
responsive to PARP inhibitor, with progression on or following PARP
inhibitor treatment
4. At least 1 prior line of therapy, but no more than 5 prior lines of
chemotherapy
4. Pancreatic Cancer Cohort 1) Histologically-proven metastatic or locally advanced
pancreatic cancer 2) At least 1 prior line of chemotherapy but no more than 4
prior lines of systemic therapy
5. Soft Tissue Sarcoma Cohort
1. Histologically-proven advanced soft-tissue sarcoma excluding all types of
adipocytic sarcoma and GIST
2. At least 1 prior line of systemic therapy (unless no standard of care
exists), but no more than 5 prior lines of systemic therapy
8. Follicular Lymphoma Cohort
1. Histologically-documented follicular lymphoma
2. Relapsed, refractory follicular lymphoma requiring therapy, after at least two
prior therapies, and if CART-treated, then evidence of progression no sooner than
3 months post CART treatment
9. Understands the procedures and requirements of the study and provides written informed
consent and authorization for protected health information disclosure
10. Willing and able to comply with the requirements of the study protocol
Key Exclusion Criteria
1. Medical Conditions
1. Known history of HIV
2. Known history of viral hepatitis B unless HBV viral load is below the limit of
quantification and off viral suppressive therapy
3. Know history of hepatitis C unless antiviral treatment with curative intent
completed and HCV viral load is below the limit of quantification.
4. Myocardial infarction or stroke within 6 months
5. Uncontrolled hypertension (systolic blood pressure (SBP) > 160 or diastolic blood
pressure (DBP) >100 on maximal medical therapy)
6. History of interstitial pulmonary disease
7. Unresolved pneumonitis
8. Grade ≥ 3 neuropathy
9. Known active central nervous system (CNS) metastases. Subjects with previously
treated CNS metastases may participate as long as clinically and radiologically
stable for at least 4 weeks after treatment, have no evidence of new or enlarging
lesions and are off steroids and asymptomatic for 28 days prior to dosing with
study medication
10. Known history of meningeal involvement or meningeal carcinomatosis
11. Spinal cord compression not definitively treated with surgery and/or radiation,
or previously diagnosed and treated spinal cord compression without evidence that
disease has been clinically stable for > 2 weeks prior to screening visit
12. Presence of clinically significant cataracts
13. Second malignancy, except treated basal cell or localized squamous skin
carcinomas, localized prostate cancer, or other malignancy that is in remission
or stable and for which patients have not been on active anti-cancer therapy for
2 years
14. Pregnant or lactating. If β-HCG is elevated, eligible if ultrasound confirms
absence of a pregnancy.
15. Dementia or significantly altered metal status
2. Prior/Concomitant Therapy
a. Prior allogeneic stem cell transplant b. On systemic antibiotic, antifungal or
anti-viral therapy c. White blood cell (WBC) growth factors administered within 14
days of screening visit d. Cancer therapy within 14 days prior to treatment with study
drug e. On narrow therapeutic index medications (see Section 7.6.1 for list of drugs)
that are sensitive substrates of CYP3A, P-gp or BCRP (or caution is warranted with
approval by the Sponsor).
f. On any drug known to prolong QTc interval (eg, certain antiarrhythmic,
antimicrobials) that cannot be discontinued or interrupted 72 hours before the Day 1
dose through Day 2, and 72 hours before the Day 15 dose until Day 16 (BID dosing) or
the Day 22 dose until Day 23 (QD dosing), in Cycle 1 (see Section 7.6.1 for a list of
drugs).
g. On systemic corticosteroid treatment for non-tumor indication at a daily dose
equivalent to >10mg of Prednisone
3. Prior/Concurrent Clinical Study Experience
a. Participation in another clinical trial (unless in the observation phase, or an
observational study), or exposure to any investigational agent within 14 days prior to
treatment with study drug
4. Laboratory assessments
1. Complete blood count (CBC):
Monotherapy and Chemotherapy Combinations 1 and 2:
1. ANC < 1.0 × 10^9/L
2. PLT < 75 × 10^9/L
3. Hgb < 9.0 g/dL
Chemotherapy Combination Group 3:
1) ANC < 1.5 × 10^9/L 2) PLT < 100 × 10^9/L 3) Hgb < 9.0 g/dL
Monotherapy and Chemotherapy Combination Groups 1 and 2:
2. Calculated Creatinine clearance (Cockcroft-Gault) < 40 mL/min
Chemotherapy Combination Group 3:
b. Calculated Creatinine clearance (Cockcroft-Gault) < 50 mL/min c. Hepatic function
1. AST > 2.0 × ULN
2. ALT > 2.0 × ULN d. Total bilirubin > 1.5 x ULN e. Albumin < 2.8 g/dL 5. ECG Exclusion
a. Screening QTc interval > 450 milliseconds for males and QTc > 470 ms for females
(corrected by Fridericia) 6. Other Exclusions
1. Unwilling or unable to make all planned study visits
2. Unwilling or unable to provide a recent biopsy or bone marrow sample prior to
enrollment and during study; Note: certain exceptions may be permitted allowing
archival specimens prior to treatment or for subjects where a specimen is not
required for biomarker positive testing (see Sections 6.1.9.1 and 6.2.8)
3. Significant medical diseases or conditions, as assessed by the Investigators and
Cyteir that would substantially increase the risk-benefit ratio of participating
in the study. This includes but is not limited to acute myocardial infarction,
arterial thrombosis, significant gastrointestinal bleed, or unstable angina
within the last 6 months uncontrolled diabetes mellitus, current active
infections, severely immunocompromised state, and congestive heart failure New
York Heart Association (NYHA) Class III-IV, left ventricular ejection fraction
(LVEF) < 40% d: Chemotherapy Combination Group 3 only: known history of
dhydropyrimidine dehydrogenase deficiency
