Neoplasms Malignant
Conditions
Keywords
Colorectal cancer, Solid tumors, Ovarian cancer, Fallopian tube cancer, Primary peritoneal cancer
Brief summary
This is an open-label, two-part study to evaluate the safety and tolerability of combination treatment with dalotuzumab + MK-2206, dalotuzumab + MK-0752, or dalotuzumab + ridaforolimus (MK-8669). Part 1 of the study will determine the dose-limiting toxicities (DLTs) observed after administration of each of the combinations at various doses and define the maximum tolerated dose (MTD) of each combination. Part 2 of the study will assess preliminary anti-tumor activity of these combinations (at MTD) in two groups of participants with selected tumor biomarkers: one group with metastatic or recurrent platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer and one group with metastatic or recurrent colorectal cancer. The dalotuzumab + ridaforolimus and dalotuzumab + MK-2206 arms will be enriched with female platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer participants. The dalotuzumab + MK-0752 arm will be enriched with metastatic or recurrent wild-type kirsten rat sarcoma (KRAS) colorectal cancer participants. The primary hypothesis is that the DLTs observed in adult patients with locally advanced or metastatic solid tumors after administration of each of the MK-MK doublets will be dose-dependent to allow for definition of a MTD within each MK-MK doublet.
Interventions
DRUGdalotuzumab
Administered intravenously (IV) once weekly in 28-day cycles for a maximum of 6 months of study therapy
DRUGMK-0752
Administered orally (PO) weekly in 28-day cycles for a maximum of 6 months of study therapy
DRUGridaforolimus
Administered PO daily for 5 consecutive days per week in 28-day cycles for a maximum of 6 months of study therapy
DRUGMK-2206
Administered PO weekly in 28-day cycles for a maximum of 6 months of study therapy
Sponsors
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants must not have any medical conditions that may impact compliance with the protocol, limit interpretation of study results, or pose an unacceptable medical risk. * Participant must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (EGOG) Performance Scale. * Participant is able to swallow capsules and has no condition that will preclude swallowing and absorbing oral medications on an ongoing basis. * Participant has no history of a prior malignancy with the exception of cervical intraepithelial neoplasia; basal cell carcinoma of the skin; adequately treated localized prostate carcinoma with prostatic specific antigen (PSA) \< 1.0; or has undergone potentially curative therapy with no evidence of that disease for five years, or is deemed at low risk for recurrence by his/her treating physician. * Participant has at least one measurable metastatic or recurrent lesion according to Response Criteria in Solid Tumors (RECIST). Part 1: * Participant must have a histologically-confirmed metastatic or locally advanced solid tumor that has failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist, or participant is not a candidate for standard therapy, or is unwilling to undergo standard therapy. There is no limit on the number of prior treatment regimens. Part 2: * A female participant assigned to the dalotuzumab + MK-2206 or dalotuzumab + ridaforolimus treatment arms must have histologically-confirmed metastatic or recurrent platinum-resistant ovarian cancer, fallopian tube cancer, or primary peritoneal cancer that has failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist, or participant is not a candidate for standard therapy, or is unwilling to undergo standard therapy. Participants may have received any number of prior treatment regimens. * A participant assigned to the dalotuzumab + MK-0752 treatment arms must have histologically-confirmed metastatic or recurrent wild-type KRAS colorectal cancer that has failed to respond to standard therapy, progressed despite standard therapy, or for which standard therapy does not exist, or participant is not a candidate for standard therapy, or is unwilling to undergo standard therapy. Participants may have received any number of prior treatment regimens. * Participant agrees to provide archival tumor tissue sample or undergo biopsy for analysis of gene expression levels.
Exclusion criteria
* Participant has had chemotherapy, radiotherapy, or biological therapy (including monoclonal antibodies) within 4 weeks prior to study Day 1 (6 weeks for nitrosoureas or mitomycin C) or who has not recovered from adverse events due to agents administered more than 4 weeks earlier, or major surgery \<4 weeks earlier. * Participant is currently participating or has participated in a study with an investigational compound or device within 28 days, or 5X half-life of the investigational compound (excluding monoclonal antibodies), whichever is longer, of initial dosing on this study. Participants previously treated with a monoclonal antibody will be eligible to participate after a 28 day washout period. * Participants with known central nervous system (CNS) metastases and/or carcinomatous meningitis are excluded. * Participant has significant or uncontrolled cardiovascular disease, including New York Heart Association (NYHA) Class III-IV heart failure, unstable angina, or a myocardial infarction within the last 6 months. * Participant is known to have diabetes that is poorly controlled. * Participant is pregnant, breastfeeding, or expecting to conceive or father children during the study. * Participant is known to be human immunodeficiency virus (HIV)-positive. * Participant has active Hepatitis B or C infection. * Participant has symptomatic ascites or pleural effusion. * Participant requires treatment with immunosuppressive agents other than prescribed corticosteroids at stable doses for at least two weeks prior to the first dose of study drug. * Participant requires treatment with medication(s) that strongly or moderately induce or inhibit cytochrome P450. * Participant is using growth hormone or growth hormone inhibitors. * Participant requires treatment with therapeutic warfarin.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose-limiting Toxicities (DLTs) | Cycle 1-28 Days | DLTs were defined as follows: 1) non-hematological toxicity ≥Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 except for Grade 3 nausea, vomiting, diarrhea, and/or dehydration; Grade 3 or 4 hyperglycemia; alopecia; inadequately treated hypersensitivity reactions; dalotuzumab infusion-related reactions; Grade 3 transaminases ≤1 week in duration; or clinically non-significant, treatable or reversible lab abnormalities; 2) Grade 4-5 hematologic toxicity, with the exception of Grade 4 neutropenia \<6 days in duration; 3) Grade 3 or Grade 4 neutropenia with fever \>38.5 degrees C; 4) Grade 4 thrombocytopenia ≤25.0 x 10\^9/Liter; 5) drug-related adverse experience leading to a dose modification during Cycle 1; 6) unresolved drug-related toxicity that causes ≥3 week delay of the next scheduled dose of study medication; 7) persistent increases in QTc interval \>60 milliseconds from baseline, or clinically significant bradycardia. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Whose Best Response is a Partial Response (PR) or Complete Response (CR) | Up to 7 months | Best response was determined for the maximum tolerated dose from the start of treatment until disease progression, recurrence, or completion of 6 months of treatment. Lesions were measured by computed tomography (CT) scan or magnetic resonance imaging (MRI). Partial response (PR), defined as a tumor burden decrease of 30%, or complete response (CR) was determined using Response Criteria in Solid Tumors (RECIST) 1.1 for participants with at least one measurable target lesion at baseline. |
Participant flow
Pre-assignment details
41 participants enrolled in Part 1 (dose escalation/preliminary maximum tolerated dose \[MTD\] identification). 12 participants continued in Part 2 (preliminary anti-tumor activity assessment), and 6 new participants were enrolled in Part 2 that did not participate in Part 1 (total enrollment = 47). Study terminated prior to completion of Part 2.
Participants by arm
| Arm | Count |
|---|---|
| Dalotuzumab 7.5 mg/kg + MK-0752 1800 mg Participants received dalotuzumab 7.5 mg/kg IV weekly + MK-0752 1800 mg PO weekly in 28-day cycles for a minimum of 6 cycles until disease progression or study discontinuation. | 4 |
| Dalotuzumab 10 mg/kg + MK-0752 1800 mg Participants received dalotuzumab 10 mg/kg IV weekly + MK-0752 1800 mg PO weekly in 28-day cycles for a minimum of 6 cycles until disease progression or study discontinuation. | 13 |
| Dalotuzumab 10 mg/kg + MK-2206 90 mg Participants received dalotuzumab 10 mg/kg IV weekly + MK-2206 90 mg PO weekly in 28-day cycles for a minimum of 6 cycles until disease progression or study discontinuation. | 3 |
| Dalotuzumab 10 mg/kg + MK-2206 135 mg Participants received dalotuzumab 10 mg/kg IV weekly + MK-2206 135 mg PO weekly in 28-day cycles for a minimum of 6 cycles until disease progression or study discontinuation. | 8 |
| Dalotuzumab 10 mg/kg + MK-2206 150 mg Participants received dalotuzumab 10 mg/kg IV weekly + MK-2206 150 mg PO weekly in 28-day cycles for a minimum of 6 cycles until disease progression or study discontinuation. | 10 |
| Dalotuzumab 10 mg/kg + MK-2206 200 mg Participants received dalotuzumab 10 mg/kg IV weekly + MK-2206 200 mg PO weekly in 28-day cycles for a minimum of 6 cycles until disease progression or study discontinuation. | 3 |
| Dalotuzumab + Ridaforolimus Participants received dalotuzumab 10 mg/kg IV weekly + ridaforolimus 20 mg PO daily for 5 consecutive days per week in 28-day cycles for a minimum of 6 cycles until disease progression or study discontinuation. | 6 |
| Total | 47 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Part 1 (Dose Escalation/MTD) | Adverse Event | 0 | 2 | 0 | 0 | 1 | 1 | 0 |
| Part 1 (Dose Escalation/MTD) | Physician Decision | 0 | 1 | 0 | 1 | 0 | 0 | 0 |
| Part 1 (Dose Escalation/MTD) | Progressive Disease | 3 | 2 | 3 | 5 | 5 | 2 | 0 |
| Part 1 (Dose Escalation/MTD) | Withdrawal by Subject | 0 | 3 | 0 | 0 | 0 | 0 | 0 |
| Part 2 (Dose Confirmation/Efficacy) | Adverse Event | 0 | 1 | 0 | 0 | 0 | 0 | 3 |
| Part 2 (Dose Confirmation/Efficacy) | Physician Decision | 0 | 0 | 0 | 1 | 1 | 0 | 0 |
| Part 2 (Dose Confirmation/Efficacy) | Progressive Disease | 1 | 3 | 0 | 1 | 2 | 0 | 3 |
| Part 2 (Dose Confirmation/Efficacy) | Withdrawal by Subject | 0 | 1 | 0 | 0 | 1 | 0 | 0 |
Baseline characteristics
| Characteristic | Dalotuzumab 7.5 mg/kg + MK-0752 1800 mg | Dalotuzumab 10 mg/kg + MK-0752 1800 mg | Dalotuzumab 10 mg/kg + MK-2206 90 mg | Dalotuzumab 10 mg/kg + MK-2206 135 mg | Dalotuzumab 10 mg/kg + MK-2206 150 mg | Dalotuzumab 10 mg/kg + MK-2206 200 mg | Dalotuzumab + Ridaforolimus | Total |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 51.8 Years STANDARD_DEVIATION 4.6 | 59.0 Years STANDARD_DEVIATION 12.2 | 50.3 Years STANDARD_DEVIATION 12.7 | 60.4 Years STANDARD_DEVIATION 12 | 65.4 Years STANDARD_DEVIATION 7 | 57.3 Years STANDARD_DEVIATION 10.1 | 68.8 Years STANDARD_DEVIATION 14.1 | 60.6 Years STANDARD_DEVIATION 11.6 |
| Sex: Female, Male Female | 3 Participants | 11 Participants | 2 Participants | 4 Participants | 4 Participants | 3 Participants | 6 Participants | 33 Participants |
| Sex: Female, Male Male | 1 Participants | 2 Participants | 1 Participants | 4 Participants | 6 Participants | 0 Participants | 0 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 4 / 4 | 13 / 13 | 3 / 3 | 8 / 8 | 10 / 10 | 3 / 3 | 6 / 6 |
| serious Total, serious adverse events | 2 / 4 | 6 / 13 | 0 / 3 | 3 / 8 | 6 / 10 | 3 / 3 | 5 / 6 |
Outcome results
Primary
Number of Participants With Dose-limiting Toxicities (DLTs)
DLTs were defined as follows: 1) non-hematological toxicity ≥Grade 3 according to Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 except for Grade 3 nausea, vomiting, diarrhea, and/or dehydration; Grade 3 or 4 hyperglycemia; alopecia; inadequately treated hypersensitivity reactions; dalotuzumab infusion-related reactions; Grade 3 transaminases ≤1 week in duration; or clinically non-significant, treatable or reversible lab abnormalities; 2) Grade 4-5 hematologic toxicity, with the exception of Grade 4 neutropenia \<6 days in duration; 3) Grade 3 or Grade 4 neutropenia with fever \>38.5 degrees C; 4) Grade 4 thrombocytopenia ≤25.0 x 10\^9/Liter; 5) drug-related adverse experience leading to a dose modification during Cycle 1; 6) unresolved drug-related toxicity that causes ≥3 week delay of the next scheduled dose of study medication; 7) persistent increases in QTc interval \>60 milliseconds from baseline, or clinically significant bradycardia.
Time frame: Cycle 1-28 Days
Population: All participants who completed the first cycle of study therapy or discontinued from the study due to a DLT attributable to study therapy.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 7.5 mg/kg + MK-0752 1800 mg | Number of Participants With Dose-limiting Toxicities (DLTs) | 1 Participants |
| Dalotuzumab 10 mg/kg + MK-0752 1800 mg | Number of Participants With Dose-limiting Toxicities (DLTs) | 3 Participants |
| Dalotuzumab 10 mg/kg + MK-2206 90 mg | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
| Dalotuzumab 10 mg/kg + MK-2206 135 mg | Number of Participants With Dose-limiting Toxicities (DLTs) | 1 Participants |
| Dalotuzumab 10 mg/kg + MK-2206 150 mg | Number of Participants With Dose-limiting Toxicities (DLTs) | 3 Participants |
| Dalotuzumab 10 mg/kg + MK-2206 200 mg | Number of Participants With Dose-limiting Toxicities (DLTs) | 2 Participants |
| Dalotuzumab + Ridaforolimus | Number of Participants With Dose-limiting Toxicities (DLTs) | 0 Participants |
Secondary
Number of Participants Whose Best Response is a Partial Response (PR) or Complete Response (CR)
Best response was determined for the maximum tolerated dose from the start of treatment until disease progression, recurrence, or completion of 6 months of treatment. Lesions were measured by computed tomography (CT) scan or magnetic resonance imaging (MRI). Partial response (PR), defined as a tumor burden decrease of 30%, or complete response (CR) was determined using Response Criteria in Solid Tumors (RECIST) 1.1 for participants with at least one measurable target lesion at baseline.
Time frame: Up to 7 months
Population: All participants who received at least one dose of study therapy and had baseline data for those analyses that required baseline data. The analysis was planned to be performed on the 3 arms in Part 2 only. The study was terminated prior to completion of this analysis.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Dalotuzumab 7.5 mg/kg + MK-0752 1800 mg | Number of Participants Whose Best Response is a Partial Response (PR) or Complete Response (CR) | 0 Participants |
| Dalotuzumab 10 mg/kg + MK-0752 1800 mg | Number of Participants Whose Best Response is a Partial Response (PR) or Complete Response (CR) | 0 Participants |
| Dalotuzumab 10 mg/kg + MK-2206 90 mg | Number of Participants Whose Best Response is a Partial Response (PR) or Complete Response (CR) | 0 Participants |